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Role of miR-155 and miR-103 in Oxidative Stress in Cardiovascular Disease: A Literature Review

Submitted:

30 June 2026

Posted:

01 July 2026

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Abstract
Background/Objectives: Oxidative stress is a major contributor to the pathogenesis of cardiovascular diseases including hypertension, ischemic cardiomyopathy, heart failure. MicroRNAs (miRNAs) have been extensively investigated in various contexts, and some of them have been identified to play a role in cardiovascular disease. This review focuses on miR-103 and miR-155, two miRNAs implicated in the modulation of oxidative stress and cardiovascular remodeling. Methods: The following queries were used in PubMed since inception until May 2026: (("miR-155" OR "microRNA-155" OR miR155) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)); (("miR-103" OR "microRNA-103" OR miR103) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)). Results: A total of 7 citations for miR-103 and 79 citations for miR-155 were identified. Reviews and papers about diseases other than those on cardiac/vascular involvement were excluded. miR-155 emerges as a potential regulator of inflammatory-redox signaling, whereas miR-103 appears more closely linked to cell fate and metabolic pathways. In both cases, available evidence supports a context-dependent role that challenges simplistic classification as pro- or anti-oxidant miRNAs. Conclusions: Available evidence suggests that both miR-103 and miR-155 are important regulators of oxidative stress-related pathways in cardiovascular disease. Nevertheless, the context-dependent effects observed across different cardiovascular disorders raise concerns regarding the safety of systemic miRNA modulation-based therapeutical strategies. Future studies should clarify the determinants of this context-dependent behavior and identify the specific conditions under which these miRNAs exert protective or harmful effects, which might pave the way for the development of miRNA-based therapeutic strategies targeting oxidative stress and cardiovascular remodeling.
Keywords: 
miR-155
;  
miR-103
;  
oxidative stress
;  
cardiovascular disease
;  
hypertension
;  
Gitelman’s syndrome
Subject: 
Medicine and Pharmacology  -   Cardiac and Cardiovascular Systems

1. Introduction

Oxidative stress is defined as the imbalance between the production and accumulation of pro-oxidant and anti-oxidant species [1,2]. Among reactive oxygen species (ROS), superoxide (O₂⁻) is generated by several enzymatic sources, including NADPH oxidases, uncoupled nitric oxide synthase, xanthine oxidase, cytochrome P450, lipoxygenases and cyclooxygenases. Due to its short half-life, O₂⁻ is rapidly converted into hydrogen peroxide (H₂O₂) by superoxide dismutase 1 and 2 (SOD1/2), a more stable and membrane-permeable ROS, which can further generate highly reactive hydroxyl radicals. Besides acting as signaling molecules, ROS can react with nitric oxide to form toxic reactive species such as peroxynitrite. To counterbalance oxidative stress, cells rely on antioxidant defenses, including enzymatic scavengers, such as superoxide dismutase and glutathione peroxidase, as well as adaptive mechanisms such as autophagy, whose effects may be either protective or harmful depending on the intensity and duration of oxidative stress [2,3,4]. While oxidants are essential for pathogen killing, their excessive production induces tissue damage. Failure of the antioxidant armamentarium to successfully moderate prooxidant species, results in detrimental effects that contribute to multiple pathophysiological processes, such as aging, cancer, cardiovascular disease, kidney disease, and autoimmune diseases [1,5,6,7,8,9]. Given the high oxygen and metabolic demands of the heart, the cardiovascular system is particularly susceptible to oxidative stress. Oxidative stress plays a critical role in the pathogenesis of multiple cardiovascular diseases, such as hypertension, fibrotic and ischemic cardiomyopathy, diabetes, and pre-eclampsia and is interconnected with inflammation and senescence [10,11,12].
MicroRNAs (miRNAs) are short non-coding RNA molecules, typically 18–22 nucleotides in length, that regulate gene expression by interacting with the 3′ untranslated region (3′UTR) of target mRNAs. Through this interaction, they can suppress protein synthesis or promote mRNA degradation, thereby modulating multiple cellular processes [13,14,15]. An individual miRNA can bind to multiple transcripts, and a single transcript can be bound by various miRNAs, determining an articulate and dynamic posttranscriptional regulation [16]. Recent literature has shown that miRNAs can play a multifaceted role in the interplay between oxidative stress and cardiovascular disease [8,9].
Among these, miR-103 (also reported as miR-103-3p) belongs to the miR-103/107 family and is located on human chromosome 5 [17]. It is expressed in various cell types and has been described as an oncogenic miRNA because of its ability to enhance cellular proliferation in several cancers, including non-small cell lung cancer, breast cancer, colon cancer, and squamous cell carcinoma. Beyond its role in tumor biology, the miR-103/107 family has also been associated with hypertensive nephropathy, cardiovascular remodeling, oxidative stress, and metabolic disorders [17,18,19].
miR-155 (also reported as mir-155-5p) is a highly conserved single-stranded non-coding RNA transcribed from the B-cell integration cluster (BIC) gene located on chromosome 21. miR-155-5p derives from the 5’ arm of the precursor miRNA hairpin and is the more biologically active. Although it is predominantly expressed in hematopoietic cells, its expression has also been detected in fibroblasts, epithelial and reproductive tissues, as well as in the central nervous system [13]. This miRNA participates in a wide range of biological functions, such as immune and inflammatory responses, regulation of apoptosis and cell proliferation, maintenance of vascular homeostasis, hypertension, cardiovascular remodeling, and cancer [13,20]. Owing to its pleiotropic functions, miR-155 has emerged as a particularly complex regulator in cardiovascular pathophysiology [13,20,21].
This review aims to summarize the available evidence from in vivo/in vitro and human-based studies of the role played by miR-103 and miR-155 in oxidative stress in cardiovascular disease.

2. Search Strategy

The following queries were used in PubMed since inception until May 2026: (("miR-155" OR "microRNA-155" OR miR155) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)); (("miR-103" OR "microRNA-103" OR miR103) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)). The search produced a total of 7 citations for miR-103 and 79 citations for miR-155, one of which was recently retracted. After duplicates removal, reviews and papers about diseases other than those on cardiac or vascular involvement were excluded. Only articles in English were fully read (Table 1 and Table 2).

3. Discussion

miR-103

MiR-103 has been particularly studied in the context of cardiac damage and function. Current evidence suggests a context-dependent role of miR-103 in cardiovascular oxidative stress, with both protective and detrimental effects being reported depending on the disease model and downstream molecular targets (Table 1).
In vitro models of induced oxidative stress, H2O2 downregulated the expression of miR-103 in a time-dependent manner. Nevertheless, cells transfected with miR-103 showed increased viability and lower intracellular ROS formation in an H2O2-induced oxidative stress environment, by targeting BNIP 3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3), a mitochondrial pro-apoptotic protein involved in mitochondrial dysfunction, oxidative stress and cell death [19,23]. In endothelial coronary artery cells, the same pathway demonstrated that miR-103 inhibition aggravates pyroptosis through NLRP3 inflammasome, and was associated with higher levels of IL-1β expression. Conversely, in vitro models (cardiomyocytes) of induced oxidative stress have shown that exposure to high levels of H2O2 (500 μM) significantly increases miR-103/107 levels, which target FADD (Fas-associated death domain protein) thereby decreasing its protein expression and impairing its protective effect on necroptosis by preventing the formation of the complex RIPK1/RIPK3.
Interestingly, the protective effects observed in endothelial oxidative injury contrast with findings from ischemia/reperfusion (I/R) models, where miR-103/107 appear to promote inflammatory cell death pathways. Wang et al observed that miR-103/107 was increased in murine models of I/R and was associated with higher levels of TNF-α and IL-1β and with a worsening cardiac function. Finally, miR103/107 antagomir administration significantly reduced the necrosis area induced by H2O2 in murine models of ischemia/reperfusion (I/R) [22].
In cardiomyocytes from diabetic mice, high glucose increased miR-103-3p levels together with ROS species, and reduced SOD. H19, a long non-coding RNA worked as a sponge for miR-103-3p, thereby preventing the inhibition of ALDH2 (Aldehyde dehydrogenase 2), thus activating the PI3K/Akt protective pathway, ultimately resulting in reduced oxidative stress and apoptosis [25]. By reducing miR-103-3p, orientin, a flavonoid, exerted anti-oxidant effects [25]. Within the same pathway, in heart failure cardiomyocytes, miR-103 suppresses PTEN (phosphatase and tensin homologue), an inhibitor of AKT signaling [24], increasing ROS production and cardiac hypertrophy [24]. Interestingly, although miR-103-3p modulates different downstream targets across cardiovascular disorders, both studies converge on dysregulation of the PI3K/AKT signaling axis and oxidative stress pathways. In diabetic cardiomyopathy, miR-103-3p suppresses the antioxidant enzyme ALDH2, leading to impaired AKT-mediated cardioprotective signaling [25], whereas in pressure overload-induced heart failure it targets PTEN, resulting in excessive AKT activation and maladaptive hypertrophic remodeling [24] (Figure 1).
Human-based studies evaluating miR-103 in cardiovascular diseases are sporadic. Mir-103 levels were found to be lower in heart failure patients compared to healthy volunteers [26], but oxidative stress parameters were not assessed. Additionally, in a cohort of patients with Gitelman syndrome, a model of reduced oxidative stress, plasmatic miR-103 levels were higher than in controls [27].
Beyond cardiovascular disease, miR-103/107 have also emerged as key regulators of metabolic homeostasis through modulation of insulin sensitivity, adipocyte differentiation and fatty acid β-oxidation via Caveolin-1-dependent pathways. These findings lead to the development of anti-miR-103/107-based treatment strategies for type 2 diabetes mellitus with Non-alcoholic Fatty Liver Disease (NAFLD) - dosed in a first-in-human phase I study by Regulus’s collaboration partner AstraZeneca - and non-alcoholic steatohepatitis (NASH) [28,29,30].
Nevertheless, whether modulation of miR-103 may represent a viable therapeutic strategy in cardiovascular diseases remains uncertain, given the context-dependent effects reported across different models of oxidative stress and cardiac injury.

miR-155

Current findings do not support a univocal role for miR-155 in cardiovascular oxidative stress. Rather, its effects appear to vary according to the disease context, cellular environment and downstream molecular targets involved (Table 2).
Several studies suggest a reciprocal relationship between oxidative stress and miR-155: on one hand redox conditions seem to trigger miR-155 accumulation, while on the other hand miR-155 can promote oxidative stress. For example, in atherogenesis, miR-155 expression was found to be induced by oxLDL (but not native LDL) in macrophages, by worsening oxidative stress conditions. Moreover, miR-155 promoted ROS production in oxLDL-induced Raw264.7 cells [38]. These findings were also supported by studies conducted in endothelial cells, where antimiR-155 attenuated oxidative stress and increased NO production, thereby contrasting endothelial dysfunction [48,53].
One of the main pathways linking miR-155 and oxidative stress in cardiovascular disease is that of NFκB. In fact, miR-155 biogenesis can be induced by NFκB, but miR-155 targets can also lead to NFκB activation, thereby contributing to oxidative stress and inflammation (Figure 2).
In vitro direct and indirect evidence support this relationship. In endothelial cells from aortas derived from gestational hypoxia offspring rats, a model of pre-eclampsia, miR-155-5p levels were elevated and associated with increased expression of NADPH oxidase 2 and ROS generation, as well as impaired NO synthesis, suggesting a causal role in pre-eclampsia pathogenesis [76]. Aspirin is a preventative strategy in pre-eclampsia. In HUVECs, aspirin was reported to inhibit the TNF-α induced miR-155 biogenesis by suppressing NFκB activation, thereby reducing endothelial dysfunction, vasoconstriction and inflammation [46]. In HUVECs, Korean red ginseng extract delayed senescence, reduced oxidative stress, and blocked NFκB-dependent miR-155 biogenesis, resulting in increased eNOS expression [56], and the same pathway was confirmed in hypertensive rats [64]. In indoxyl sulfate-treated human aortic cells mimicking uremic vascular calcifications, NFκB activation induced miR-155-5p biogenesis along with an increase in Matrix Gla Protein and an increase in ROS production, both reversed by NFκB inhibition [55]. Finally, miR-155-5p was elevated in hypertensive mice’ renal arteries and endothelial cells and was accompanied by increased ROS, NFκB activation and decreased eNOS [64].
Oxidative stress can also be initiated by the inflammasome pathway, which may trigger miR-155. In mouse microglial cells, miR-155 inhibition reverted resveratrol's protective effects on oxidative stress by affecting NLRP3 inflammasome [62]. In line with this, inhibition of miR-155 suppressed NLRP3 inflammasome activation also in renal tubular cells, by targeting FOXO3a, thus reducing oxidative stress and apoptosis [47].
miR-155 was broadly studied in atherogenesis [14]. In human VSMCs miR-155 played a proatherogenic role: miR-155 inhibition abolished the effects of salusin-β on inflammation, monocyte adhesion, and ROS production in VSMCs [43]. Also in cultured human endothelial brain cells, miR-155 inhibition reduced ROS expression and increased NO production [39]. MiR-155 was demonstrated to promote vascular smooth muscle cells proliferation by inhibiting MST-2, thus favoring inflammation and oxidative stress [42]. In ApoE-/- mice, treatment with Shexiang Tongxin dropping pill (STDP) – a traditional Chinese medicine treatment for angina pectoris - was associated with a reduction in oxidative stress and inflammation and accompanied by a decrease in miR-155 levels [41].
Regarding cardiomyopathies, in mice models of fibrotic cardiomyopathy, miR-155-5p levels were associated with oxidative stress and activation of the HIF-1-α and TGF-β signaling pathways; while treatment with apigenin, an antioxidant flavonoid molecule, decreased miR-155-5p levels [63]. In cardiomyocytes transferred with extracellular vesicles derived from an ischemia-reperfusion (IR) environment, the expression of miR-155-5p was significantly increased and contributed to ferroptosis by targeting and inhibiting Nfe2l2 pathway, which regulates the expression of cytoprotective and antioxidative genes [78]. Addition of miR-155-5p mimics also facilitated oxidative stress with a reduction in NADPH levels and an increase in MDA production [78]. Ferroptosis and oxidative stress are pathological mechanism involved in cardiac damage in Sars-CoV2 infection and miR-155 was reported to play a role too [74].
Oxidative stress triggered by hyperglycemia, insulin resistance and hyperlipidemia is a pivotal contributor to the endothelial dysfunction which ultimately leads to high-mortality-burdened macro- and micro-vascular complications in diabetes [11]. In ovariectomized diabetic mice, miR-155 expression was enhanced in the macrophages along with an increase in ROS, cell apoptosis, cardiac hypertrophy and fibrosis in the heart [45]. The administration of antagomiR-155 covalently conjugated with gold nanoparticle (AuNP) successfully delivered the nucleic acids into the macrophages, increasing M2 macrophages over M1 proliferation and reducing inflammation and cardiac damage, making it a promising strategy for improving cardiac function [45]. Further research by Zhang et al observed that in HUVECs exposed to a high glucose environment, miR-155 promoted ROS generation by targeting the SIRT1/Nrf2/HO-1 pathway and induced epithelial-mesenchymal transition, suggesting a role of this miRNA in the difficult wound-healing process in diabetes [75].
miR-155 was also identified to intervene in the SOCS1 signaling pathway within the context of diabetic damage and ageing. Prieto et al showed that miR-155-5p inhibitor decreases the JAK/STAT1 signaling pathway responsible for inflammation and oxidative stress in ApoE -/-diabetic mice by upregulating SOCS1 [67]. Accordingly, SOCS1 was confirmed to be a target of miR-155 also in endothelial cells, leading to cell cycle arrest (by increasing p21) and ROS production, ultimately resulting in a pro-senescence effect [77].
On the other hand, an opposite role of miR-155 in the RAAS axis and Ang II-induced oxidative stress and cardiovascular remodeling in hypertension was proposed (Figure 3). A robust proof comes from the paper by Dupont et al who pointed out miR-155 as the most down-regulated miRNA with vascular aging in mice’ smooth muscle cells with intact mineralocorticoid receptors [44].
In mice mesenteric vessels, decrease in miR-155 was associated with a concomitant increase in MR mRNA with aging. Restoration of miR-155 in smooth muscle cells of aged MR-intact mice reduced Cav1.2, the pore-forming L-type Calcium Channel (LTCC), and Agtr1 mRNA and attenuated AT II induced vasoconstriction and oxidative stress [44]. Wu et al observed that in VSMCs cells of spontaneously hypertensive rats, miR-155-5p mimic inhibited ACE expression and reduced ROS production along with IL-1β and TNF-α expression, thereby impairing VSMCs migration and oxidative stress which contribute to maladaptive vascular remodeling in hypertension and related organ damage. However, the same effect was not detected after exogenous Ang II administration, suggesting ACE could be a direct target of miR-155-5p [52]. Tong et al confirmed the inhibitory role of miR-155-5p in VSMCs migration and oxidative stress by reporting that miR-155-5p exogenous administration reduced NOX2 and NOX4 protein expression and activity in VSMCs from spontaneously hypertensive rats by knocking down BACH1 expression, a transcriptional repressor of the cytoprotective enzyme heme oxygenase-1 (HO-1) [68]. Conversely, BACH1, which is also expressed on chromosome 21, was not identified as a target of miR-155 in the process of senescence in endothelial cells deriving from mouse aortas in the study of He et al [77]. Bernard-Harrison et al reported that in Dahl salt sensitive mice under high salt diet, miR-155 serum and aortic levels were lower than in Dahl salt-sensitive mice under low salt diet, while AT1R levels were higher, together with p-MYPT1/MYPT-1 and proteinuria, suggesting a deleterious role of low levels of miR-155 [73]. In spontaneously hypertensive rats, miR-155 was instead elevated, while AT1R levels and proteinuria were decreased, suggesting that miR-155 might contribute to keeping AT1R levels low, thereby limiting Ang II-oxidative stress mediated kidney damage despite hypertension [73]. Song et al observed that treatment with a soy-bean derived antihypertensive (LSW) reduced oxidative stress and inflammation while increasing miR-155-5p compared to Ang-II- and control- treated HUVECs cells [61]. Moreover, in the context of myocardium injury, miR-155 was increased and played a regulatory role in oxidative stress-induced necrosis in cardiomyocyte progenitor cells by targeting receptor-interacting protein 1 (RIP1) [31]. Finally, in HUVECs and PBMCs, miR-155-5p was up-regulated along with antioxidant genes’ expression as a result of hydroxyurea, an antioxidant agent prescribed in sickle-cell anemia [57].
miR-155 was also evaluated in a broad number of small patient cohorts, and the relationship with oxidative stress is mostly of associative nature. For example, miR-155 was observed to be up-regulated in placentas from pre-eclamptic women vs controls and affects cysteine-rich protein 61 (CYR61), a significant premature angiogenesis component in gestation [79]. Another example are Friedrich’s ataxia patients, where a polymorphic miR-155 binding site in AGTR1 was associated with cardiac hypertrophy, while in CD14+ monocytes from patients affected by coronary disease, miR-155 expression was up-regulated [38]. Additionally, a decrease in miR-155 expression was detected with aging [80]. Serum miR-155 predicted the BP treatment response to MR antagonists in elderly humans [44]. Oxidative stress development is also associated with cigarette smoking. Interestingly, miR-155 levels were statistically increased right after smoking in a cohort of smokers [53]. Duisenbeck et al reported that in diabetic patients, miR-155 level was higher than in healthy subjects and positively correlated with HbA1c and glycaemia. However, no significant difference was detected with diabetic patients with macrovascular complications. Intriguingly, the same authors proposed a predictive model for the diagnosis of diabetes in obese subjects, based on the combination of miR-210, miR-155, glutathione peroxidase, lipid peroxidation and BMI [70], suggesting a close relationship between obesity, diabetes and oxidative stress. The relationship between miR-155, glucose levels and oxidative stress parameters was confirmed in a study conducted in metabolic syndrome patients [71]. Moawad et al. compared coronary heart disease patients with healthy subjects and showed higher levels of miR-155 along with higher MDA and lower SOD levels in the first group [72]. Furthermore, in a cohort of patients with Gitelman syndrome, plasma miR-155 levels were higher than in controls, proposing a role of this miRNA in their well-established protection against Ang II-induced cardiovascular remodeling [27]. Finally, given the location of miR-155 gene on chromosome 21, multiple studies in Down syndrome (DS) – a population burdened by a higher prevalence of cardiovascular disease and higher risk for chemotherapy cardiotoxicity - have been conducted [20]. However, miR-155 expression was not different in ex vivo studies conducted on heart samples from DS heart donors vs non-DS heart donors. However, in non-DS donors, there was a positive association between BACH1 mRNA levels and miR-155 expression. This suggested that in the myocardium of euploid subjects, increasing levels of the inhibitor miR-155 would be necessary to target increasing levels of the BACH1 mRNA transcript. In contrast, the lack of a significant association between BACH1 mRNA and miR-155 levels in samples from donors with-DS was proposed to be indicative of a disruption in this layer of control against oxidative stress in DS [36].
Overall, evidence on the role of miR-155 in oxidative stress in cardiovascular disease is broad and controversial, suggesting that miR-155 may function as a redox rheostat rather than as a purely pro- or anti-oxidant mediator.
So far, only therapeutics based on miR-155 antagonists have been developed and mostly in cancer fields [14]. One example is cobomarsen, which was moved into phase II for T-cell leukemia/lymphoma [81]. Moreover, MRG-107 is an antagomir of miR-155 aimed to inhibit the activity of miR-155 in immune mechanisms and inflammation in amyotrophic lateral sclerosis (ALS) with promising results in preclinical models [30]. In fibrosis research, local injection of antagomiR-155 was demonstrated to inhibit the Wnt/β catenin and AKT signaling pathways, thereby reducing fibrosis [82]. Regarding cardiovascular research, knocking out miR-155 in atherogenic apolipoprotein E knockout (ApoE KO, or ApoE-/-) mice resulted in the establishment of the first metabolically healthy obesity (MHO) mouse model with decreased aortic atherosclerosis, increased obesity, white adipose tissue hypertrophy and non-alcoholic fatty liver disease but without insulin resistance [83]. On the other hand, promoting the expression of miR-155 was proposed as an effective strategy to regulate blood pressure in hypertensive disorders [14].

4. Conclusions and Future Directions

Although miR-103 and miR-155 are both involved in oxidative stress pathways, miR-155 emerges as a potential regulator of inflammatory-redox signaling, whereas miR-103 appears more closely linked to cell fate and metabolic pathways. In both cases, available evidence supports a context-dependent role that challenges a simplistic classification as pro- or anti-oxidant miRNAs.
One of the major unresolved issues is the context-dependent behavior of miR-155 and miR-103 across different cardiovascular disorders. Future studies should clarify whether the divergent pro- and anti-oxidant effects depend primarily on cell type, disease stage, inflammatory milieu or compensatory adaptive responses. For example, most of the reported effects related to oxidative stress have been demonstrated in acute settings, and studies on long-standing mimic/inhibition of specific miRNAs are lacking. A substantial proportion of the available literature remains associative, with limited mechanistic validation through gain- and loss-of-function approaches. In addition, only few targets of miR-155 and miR-103 within the context of oxidative stress were identified. The in vitro models of oxidative stress were mostly artificially induced via H2O2 exposure and therefore only partially mimic the real oxidative conditions of cells. Importantly, studies based on humans are the minority, are characterized by low standardization, and predominantly yielded indirect evidence linking miR-155 to oxidative stress. Clinical studies investigating miR-103 relationship with oxidative stress are not available yet. Moreover, most human-based studies are based on small cohorts of patients, and longitudinal clinical investigations are currently lacking. While anti-miR-103 strategies have already entered clinical development for metabolic diseases, miR-155-based therapies have mainly been investigated in cancer and inflammatory disorders.
Collectively, available evidence suggests that both miR-103 and miR-155 are important regulators of oxidative stress-related pathways in cardiovascular disease. Nevertheless, the context-dependent effects observed across different cardiovascular disorders raise concerns regarding the safety of systemic miRNA modulation-based therapeutical strategies. Therefore, future studies should be aimed at clarifying the determinants of this context-dependent behavior and at identifying the specific conditions under which these miRNAs exert protective or harmful effects. Such knowledge will not only improve our understanding of the pathophysiological role of miR-103 and miR-155 in cardiovascular disease but may also pave the way for the development of novel miRNA-based therapeutic strategies targeting oxidative stress and cardiovascular remodeling.

Author Contributions

Conceptualization, M.C. and L.A.C; methodology, M.C.; investigation, M.C., L.F.S.; I.C., G.D., M.Ce., G.P., L.A.C.; resources, F.N. and L.A.C.; writing—original draft preparation, M.C. and L.A.C.; writing—review and editing, M.C. and L.A.C..; supervision, L.A.C. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded in part by the Department of Medicine (DIMED), University of Padua Research Grant, Decreto Rep. n. 269/2025, Prot 11128 29/10/2025 to GD.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

authors declare no conflicts of interest.

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Figure 1. Context-dependent effects of miR-103 on cardiovascular oxidative stress. In endothelial cells exposed to oxidative stress, reduced miR-103 expression contributes to mitochondrial dysfunction and inflammasome activation through BNIP3 and NLRP3 signaling, whereas restoration of miR-103 attenuates ROS production, IL-1β release and cell injury. Conversely, in pathological settings such as ischemia/reperfusion (I/R) injury, diabetic cardiomyopathy and pressure overload-induced heart failure, increased miR-103/107 expression promotes inflammatory cell death, oxidative stress and maladaptive remodeling by targeting FADD, ALDH2 and PTEN-dependent pathways. Collectively, current evidence indicates that miR-103 acts as a context-dependent regulator of oxidative stress and cell fate decisions in cardiovascular disease.
Figure 1. Context-dependent effects of miR-103 on cardiovascular oxidative stress. In endothelial cells exposed to oxidative stress, reduced miR-103 expression contributes to mitochondrial dysfunction and inflammasome activation through BNIP3 and NLRP3 signaling, whereas restoration of miR-103 attenuates ROS production, IL-1β release and cell injury. Conversely, in pathological settings such as ischemia/reperfusion (I/R) injury, diabetic cardiomyopathy and pressure overload-induced heart failure, increased miR-103/107 expression promotes inflammatory cell death, oxidative stress and maladaptive remodeling by targeting FADD, ALDH2 and PTEN-dependent pathways. Collectively, current evidence indicates that miR-103 acts as a context-dependent regulator of oxidative stress and cell fate decisions in cardiovascular disease.
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Figure 2. Proposed NFκB-dependent pro-oxidant signaling mediated by miR-155 in cardiovascular disease. Oxidative and inflammatory stimuli, including ROS, TNF-α and Ang II, activate NFκB, which promotes miR-155 expression. Increased miR-155 contributes to oxidative stress and vascular injury through multiple mechanisms, including suppression of SOCS1 with subsequent activation of JAK/STAT signaling, stimulation of the NLRP3 inflammasome pathway, and inhibition of eNOS resulting in reduced nitric oxide bioavailability. Collectively, these pathways promote inflammation, endothelial dysfunction, cellular senescence and ROS generation, ultimately contributing to hypertension, vascular remodeling and atherosclerosis.
Figure 2. Proposed NFκB-dependent pro-oxidant signaling mediated by miR-155 in cardiovascular disease. Oxidative and inflammatory stimuli, including ROS, TNF-α and Ang II, activate NFκB, which promotes miR-155 expression. Increased miR-155 contributes to oxidative stress and vascular injury through multiple mechanisms, including suppression of SOCS1 with subsequent activation of JAK/STAT signaling, stimulation of the NLRP3 inflammasome pathway, and inhibition of eNOS resulting in reduced nitric oxide bioavailability. Collectively, these pathways promote inflammation, endothelial dysfunction, cellular senescence and ROS generation, ultimately contributing to hypertension, vascular remodeling and atherosclerosis.
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Figure 3. Proposed ntioxidant and vasculoprotective effects of miR-155 through modulation of the renin–angiotensin system and BACH1 signaling. Increased miR-155 expression promotes the degradation of AT1R, ACE and BACH1 mRNAs. Downregulation of AT1R attenuates Ang II-mediated signaling, reducing NOX2/4 activation, ROS generation and downstream vascular inflammation, oxidative stress and remodeling. In parallel, repression of BACH1 relieves its inhibitory effect on heme oxygenase-1 (HO-1), enhancing antioxidant defenses and further limiting ROS accumulation. Collectively, these mechanisms contribute to the protective role of miR-155 against oxidative stress-induced cardiovascular damage.
Figure 3. Proposed ntioxidant and vasculoprotective effects of miR-155 through modulation of the renin–angiotensin system and BACH1 signaling. Increased miR-155 expression promotes the degradation of AT1R, ACE and BACH1 mRNAs. Downregulation of AT1R attenuates Ang II-mediated signaling, reducing NOX2/4 activation, ROS generation and downstream vascular inflammation, oxidative stress and remodeling. In parallel, repression of BACH1 relieves its inhibitory effect on heme oxygenase-1 (HO-1), enhancing antioxidant defenses and further limiting ROS accumulation. Collectively, these mechanisms contribute to the protective role of miR-155 against oxidative stress-induced cardiovascular damage.
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Table 1. Summary of evidence about miR-103 role in oxidative stress in cardiovascular disease.
Table 1. Summary of evidence about miR-103 role in oxidative stress in cardiovascular disease.
Author Year In vitro/in vivo model Pathway Final effect
Wang J. et al [22] 2015 H9c2 CELLS high levels of H2O2 (500 mM) significantly increase the expression of miR-103/107
miR-103/107 are involved in H2O2-induced necrosis by targeting FADD		 pro-oxidant and pro-necrotizing
mice model of I/R (ischemia/reperfusion) knockdown of miR103/107 decreases the expression levels of inflammatory cytokines TNF alfa and interleukin b
in the I/R mice models, miR-103/107 antagomir administration resulted in a reduction in the myocardial necrosis, reduced myocardial infarct sizes and reduced plasma levels of cardiac necrosis biomarker troponin T, without affecting myocardial apoptosis; reduced cardiac fibrosis; ameliorated cardiac function
Xu et al [19] 2015 Human umbilical vein endothelial cells (HUVECs) H2O2 (5,10,25,50,100 and 100 mM) downregulated the expression of miR-103 in a time- and dose-dependent manner
cells transfected with miR-103 showed increased viability and lower intracellular ROS formation in an H2O2-induced oxidative stress environment, by targeting BNIP3
miR-103 was upregulated following pretreatment with salidroside (an antioxidant agent) in an H2O2-induced oxidative stress		 anti-oxidant and anti-apoptotic
Wang Y. et al [23] 2020 human coronary artery endothelial cells (HCAECs) H2O2-induced oxidative stress downregulates miR-103 in a time-dependent manner
pre-103 reduced the accumulation of autophagic ubiquitin-like p62 and LC3II proteins
miR-103 inhibitor reduces cell survival rate in H202 induced oxidative stress reducing p-mTOR/mTOR expression, thus inhibiting end-stage autophagy
miR-103 inhibition increased the expression of BNIP3
miR-103 inhibition aggravates pyroptosis through NLRP3 inflammasome, and was associated with higher levels of IL-1β		 anti-oxidant
Logan et al [16] 2021 neonatal mice isoflurane and CO increase miR-103 levels vs air anti-apoptotic
Zhang et al [24] 2022 cardiomyocytes from transverse aortic constriction (TAC) mice in TAC mice miR-103-3p increases significantly and is associated with higher ROS levels, cardiac hypertrophy, increase of ANP and beta MHC, worsening of cardiac function pro-oxidant, pro-hypertrophic
primary neonatal mouse cardiomyocytes lnccytb acted as a competitive endogenous RNA via sponging miR-103-3p
HEK293T cells miR-103-3p targets PTEN to promote isoprenaline-induced hypertrophy and ROS generation
cardiac stress → ↓ lnccytb → ↑ miR-103-3p → ↓ PTEN → ↑ AKT → ↑ ROS , hypertrophy, heart failure
Wang X. et al [25] 2025 HL-1 mouse cardiomyocytes the myocardium of diabetic mice showed upregulation of miR-103-3p
high glucose enhanced ROS and MDA levels, decreased SOD and increased miR-103-3p , which were reversed by orientin (an antioxidant agent)
H19 overexpression inhibited high glucose-triggered ROS production in HL-1 cells, but miR-103-3p overexpression or ALDH2 depletion negated the effects of H19 overexpression
High glucose → ↑ miR-103-3p → ↓ ALDH2 → ↓ PI3K/AKT → ↑ ROS		 pro-apoptotic and pro-oxidant
Table 2. Summary of evidence about miR-155 role in oxidative stress in cardiovascular disease.
Table 2. Summary of evidence about miR-155 role in oxidative stress in cardiovascular disease.
Author Year in vitro/in vivo/human-based studies Pathway Final effect
Liu et al [31] 2011 cardiomyocyte progenitor cells miR-155 inhibits oxidative-stress-induced necrosis by targeting RIP-1 anti-necrotic
Kelly et al [32] 2011 Friedrich's ataxia patients polymorphism rs5186 - which increases expression of AGTR1 by altering the binding site for miR-155 - is associated with cardiac hypertrophy (to which oxidative stress contributes) anti-hypertrophic (indirectly)
Munoz-Pacheco et al [33] 2012 THP-1 cells (human monocytic cell line) phorbol-12-myristate-13-acetate (PMA) treated THP-1 cells showed increased levels of ROS and of miR-155; ezetimibe-induced inhibition of THP-1 cell differentiation was associated with the down-regulation of the expression of mir-155, mir-222, mir-424 and mir-503; MAP Kinase and NF-B pathways, as well as oxidative stress, are involved in this effect pro-oxidant (indirectly)
Jia et al [34] 2014 ApoE-/- mice NR1 treatment in ApoE-/- mice induced higher expression of SOD, GSH, reduced ROS, and pro-inflammatory cytokines, along with the reduction of miR-155 (not statistically significant) not statistically significant
Liu D et al [35] 2014 patients with intracranial aneurysms miRNA profile differed in intracranial aneurysms vs superficial temporal arteries (miR-155 not significantly) not statistically significant
Hefti et al [36] 2014 hearts from Down syndrome and non-Down Syndrome donors Difference in expression of miR-155 and BACH1 pro-oxidant (indirectly)
Costantino et al [37] 2016 diabetic mice miR-155 (among those involved in oxidative stress) was REDUCED in diabetic mice, and the impairment persisted despite normalization of blood glucose levels pro-oxidant (indirectly)
Tian et al [38] 2014 ApoE-/- mice
 the level of miR-155 in the plasma of atherosclerotic mice is increased and oxLDL effectively induces the expression of miR-155 in macrophages.
miR-155 mediates oxLDL-induced lipid uptake and reactive oxygen species (ROS) production of macrophages, by targeting HBP1. Repression of HBP1 by miR-155 transforms macrophages into foam cells 		pro-oxidant; pro-atherosclerotic
patients with coronary heart disease miR-155 expression is up-regulated in CD14+ monocytes from patients with coronary heart disease
miR-155 inhibition decreases lipid-loading in macrophages and reduces atherosclerotic plaques in ApoE-/- mice and is associated with a reduction in TNF-alfa and IL-6 expression
Liu Y. et al [39] 2015 human brain micro vessel endothelial cells HBMECs silencing of miR-155 decreases apoptosis and ROS production, while promoting NO generation in both vehicle and ox-LDL treated cells via the PI3K/Akt signaling pro-oxidant and pro-apoptotic
Seong-Min et al [40] 2015 Smokers vs non-smokers male smokers showed 3 fold higher levels of miR-155 in HDL; 8 weeks of vitamin C reduced miR-155 levels in HDL in smokers and non-smokers male pro-oxidant (indirectly)
Xiong et al [41] 2015 ApoE -/- mice Shexiang Tongxin dropping pill (STDP) treatment is associated with a significant reduction in MDA, ox-LDL, increased SOD, reduced ROS, and pro-inflammatory cytokines and with a significant reduction in miR-155 expression in ApoE -/- mice aorta pro-oxidant and pro-inflammatory (indirectly)
Yang et al [42] 2015 mice femoral arteries injured vessels in miR-155-/- mice showed decreased proliferation; injured arteries showed higher expression of miR-155 vs uninjured arteries
miR-155 down-regulates MST2 which competes with MEK for RAF-1 binding, resulting in ERK1/2 activation and ultimately NFκB and p47phox activation		 pro-inflammatory and pro-oxidant
Sun et al [43] 2016 Human aortic VSMCs salusin-beta (a stimulator of the progression of atherosclerosis) increased miR155 expression; miR-155 inhibition prevented salusin-beta effects on ACAT-1 and VCAM-1 expressions, p65-NFkB nuclear translocation, lipid accumulation, monocytes adhesion and ROS production in VSMCs pro-oxidant and pro-atherogenic
DuPont et al [44] 2016 smooth muscle cells-MR-KO mice miR-155 was downregulated with aging and associated with an increase in MR (mineralcorticoid receptor) expression
miR-155 restoration reduced Cav1.2 and Agtr1 expression, attenuating AT2-induced vasoconstriction and oxidative stress		 anti-oxidant, anti-hypertensive
HEK293 cells MR repressed miR-155 promoter in a ligand-independent way
Jia et al [45] 2017 hearts from ovariectomized diabetic mice MIr-155 expression was higher in diabetic ovariectomized mice than diabetic mice not ovariectomized, together with an increased M1 polarization pro-inflammatory, pro-oxidant
RAW264.7 cells AuNP-mediated miR155 antagonist delivery promotes M2 polarization with a reduction in IL-1β and increase in IL-10 and a restoration of the cardiac function and an increase in the vascular density
Kim et al [46] 2017 HUVECs Aspirin inhibits ROS-mediated vasoconstriction, inflammation and endothelial dysfunction by down-regulating miR-155 in pre-eclampsia pro-oxidant and pro-inflammatory
Wu et al [47] 2018 NLRP3-/- and wild type male mice miR-155 was up-regulated in renal tissue and HK-2 cells exposed to chronic intermittent hypoxia pro-oxidant and pro-inflammatory
HK-2 cells inhibition of miR-155 suppressed NLRP3 inflammasome activation in renal tubular cells, by targeting FOXO3a, thereby reducing oxidative stress and apoptosis
overexpression of miR-155 promoted oxidation and NLRP3 pathway		 pro-oxidant and pro-apoptotic
Chen et al [48] 2019 endothelial cells miR-155 inhibition promotes endothelial cells proliferation and reduces SOD expression; miR-155 regulates autophagy via decreasing the expression of ATG5 pro-oxidant and anti-proliferative
Marzano et al [49] 2019 iPSK3 and Alzheimer’s-associated SY-UBH lines differential expression of miR-155 in extracellular vesicles among different cells groups potentially association with anti-oxidant and neuroprotective effects
Scoditti et al [50] 2019 human Simpson–Golabi–Behmel Syndrome (SGBS) adipocytes olive oil polyphenol hydroxytyrosol counteracts miR-155-5p expression and prevents NF-kB activation and production of ROS pro-oxidant (indirectly)
Zhang W et al [51] 2020 rats within 24 hours from intracranial hemorrhage, miR-155 increases along with IL-1β, IL-6, TNF-α and oxidative stress products in the parietal and hippocampus. MiR-155 inhibitor attenuates this elevation, increases VEGF expression and improves neurological function pro-oxidant and pro-inflammatory
Wu N et al [52] 2020 spontaneous hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) miR-155-5p mimic inhibited ACE, NOX2, IL-1β, TNF-α expression in VSMCs of spontaneous hypertensive rats
exogenous Ang II increased miR-155-5p expression in WKY rats but not in SHR		 anti-oxidant, anti-inflammatory
Frati et al [53] 2020 smokers plasmatic miR-155 is significantly increased shortly after smoking pro-oxidant and vasoconstrictive
HUVECs miR-155 accumulates in medium after exposure to cigarette smoke condensate
anti-miR-155 attenuated condensate smoke-induced angiogenesis, oxidative stress and NO production
miR-155 mimic decreased cell viability, impaired capillary network formation and impaired capillary network, reduced VEGF and eNOS		 pro-oxidant
Cai et al [54] 2020 TNF-α -/- mice TNF-α KO DOCA/Salt-hypertensive mice showed reduced oxidative stress, increased eNOS expression and inhibited miR-155 expression in the aorta pro-oxidant and pro-inflammatory (indirectly)
He et al [55] 2020 human aortic smooth muscle cells HASMCs indoxyl-sulfate (uremic toxin) increases miR-155-5p expression with a corresponding increase in ROS and decline in Matrix Gla protein (MGP), which is reversed by NFκB inhibition pro-oxidant and pro-inflammatory
Kim et al [56] 2020 HUVECs Korean Red ginseng extract (KRGE) induced HO-1 and inhibited NFkB-dependent miR-155-5p biogenesis with the downregulation of eNOS
miR-155-5p levels were increased in senescent HUVECs vs young cells; and the increase was recovered by KRGE or NFκB inhibitor 		pro-oxidant and pro-inflammatory
Santana et al [57] 2020 HUVECs and PBMCs hydroxyurea reduces intracellular ROS and increases antioxidant enzymes (SOD1, GSR, GPX1), contemporarily up-regulating miR-155-5p expression anti-oxidant (indirectly)
Norouzi et al [58] 2020 mouse brain derived
microvessel endothelial, bEnd.3 and human U251 GBM cells		 doxorubicin increases oxidative stress and apoptosis, concomitantly with a decrease in miR-155 anti-oxidant (indirectly)
Witvrouwen et al [59] 2021 pre-eclampsia and healthy pregnant women miR-155 was not significantly different between groups not statistically significant
Nguyen et al [60] 2021 human VSMCs miR-155-5p (both intracellular and exosomal) decreases in senescent cells and is associated with elevated oxidative stress pro-oxidant (indirectly)
Song et al [61] 2021 HUVECs and VSMCs miR-155 expression decreased in extra vesicles from HUVECs treated with AT II, compared to the control and LSW treatment and was associated with increase in oxidative stress and inflammatory cytokines; LSW treatment reduces oxidative stress and increases miR-155-5p anti-oxidant (indirectly)
Tufekci et al [62] 2021 N9 mouse microglial cells Resveratrol down-regulates inflammasome-induced miR-155 expression, inhibits NFκB translocation, activates AMPK/Sirt1 pathways and ameliorates intracellular and mitochondrial ROS production
miR-155 inhibition reverses protective role of resveratrol by affecting NLRP3, IL-1b and IL-18
AMPK and Sirt1 pathways inhibition reverses the protective effect of resveratrol on miR-155 expression		 pro-oxidant
Wang F. et al [63] 2022 mouse model of myocardial fibrosis Apigenin reduces oxidative stress and miR-155-5p expression in isoproterenol-induced myocardial fibrotic mice pro-oxidant and profibrotic
CFs cell line miR-155-5p inhibitor reduces the TGF-β1/smad
miR-155-5p mimic significantly reduces HIF-1α
Wang X. et al [64] 2022 Endothelial cells from two kidneys one clip, hypertensive rats miR-155-5p expression was higher in hypertensive rats vs control rats and accompanied by a decrease in eNOS and an increase in oxidative stress and was reversed by t-AUB treatment; results were confirmed by miR-155-5p inhibitor and mimics. pro-oxidant
Aykutlu et al [65] 2022 human retinal pigmented epithelium cell line age related macular degeneration showed a higher expression of miR-155, which is inversely related with miR-184, oxidative stress and apoptosis pro-oxidant (indirectly)
Constantin et al [66] 2022 Human-induced pluripotent stem cell-derived cardiomyocytes hiPSC-CMs and bone marrow derived stem cells BMMSC no difference in miR-155 expression in the extra vesicles of the two types of cells nor vs treatment with ATII and TGF-β not statistically significant
Prieto et al [67] 2023 mouse mesangial cells miR-155-5p promotes the proliferation and migration of mesangial cells under inflammatory and hyperglycemic conditions; increases SOCS1 and impairs STAT1/3 phosphorylation pro-oxidant
ApoE-DM mice and WT mir-155-5p inhibitor upregulates SOCS1 expression and decreases STAT1/3
mIr-155-5p is positively associated with NOX2 and NOX4 levels and negatively with SOD1 and catalase
Tong et al [68] 2023 Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) miR-155-5p is lower in primary VSMCs from spontaneously hypertensive rats than WKY rats
miR-155-5p exogenous administration mitigates oxidative stress (NOX2 and NOX4 protein expression and activity and decrease in ROS levels) in VSMCs from SHR
miR-155-5p overexpression inhibited BACH1 in VSMCs from both SHR and WKY rats, with a reduction in oxidative stress and cell migration; with an inverse pattern with mIR-155-5p inhibitor		 anti- oxidant
Beltramo et al [69] 2023 immortalized human microglial cells and human retinal endothelial cells miR-155 expression was higher in cells exposed to M1 cytokines pro-oxidant
Duisenbek et al [70] 2024 human-based study (diabetic patients) miR-155 levels is higher in diabetic patients than in controls and is positively associated with HbA1c and glucose levels; predicts diabetes in obese subjects along with glutathione peroxidase and lipid peroxidation levels pro-oxidant
Khedr et al [71] 2024 human-based studies (metabolic syndrome patients) miR-155 levels decreased after 6 months of green coffee treatment together with inflammation and oxidative stress parameters; miR-155 positively correlates with HbA1c, glucose levels and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance)
Moawad et al [72] 2024 human-based study (coronary heart disease patients) coronary heart disease patients showed higher levels of miR-155 together with higher MDA and lower SOD
Harrison- Bernard et al [73] 2024 Dahl salt-sensitive (DS) and spontaneously hypertensive rats (SHR) DS-high salt rats showed significantly higher levels of aortic and kidney AT1R, p-JAK/JAK2, p-MYPT1/MYPT1, Arhgef and proteinuria, lower kidney and serum klotho and lower serum and aorta miR-155 vs DS-low salt rats. SHR showed higher levels of miR-155 with no higher levels of AT1R. anti-oxidant
Alizadeh Saghati et al [74] 2024 human cardiac tissue hearts of patients with COVID-19 present increased activation of ferroptosis and oxidative stress; miR-155 is involved in this pathway pro-oxidant
Zhang Y. et al [75] 2024 HUVECs and HEK293 cells miR-155 mimic increases ROS levels and decreases a-SMA and Vim; miR-155-5p inhibitor increases SIRT1, Nrf2 and HO-1 expression. pro-oxidant
Zhao M. et al [76] 2024 ex vivo primary vascular endothelial cells from thoracic aortas of rats offspring hypoxia offspring-derived endothelial cells showed higher levels of miR-155-5p; miR-155-5p mimic increased miR-155-5p expression; miR-155-5p inhibitor reduces ROS production in offspring endothelial cells and reduces NO synthesis pro-oxidant
He J et al [77] 2025 bone marrow derived cells M1 polarized; endothelial cells from mouse aorta endothelial cells co-culture with M1 exosomes carrying high levels of miR-155 had a pro-senescence effect by targeting SOCS1 activating JAK2/STAT3 and increasing ROS production in endothelial cells
miR-155 mimic decreases SOCS1 but does not target BACH1 or IKBKE		 pro-oxidant and pro apoptotic and pro-senescent
Ge et al [78] 2026 cardiomyocytes from mice miR-155-5p is associated with ferroptosis and is increased in cells after incubation with H2O2; miR-155-5p targets NFE2L2, thereby inhibiting the promotion of expression of protective and antioxidative genes pro-oxidant and pro-ferroptotic
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