Objectives: To evaluate atrial fibrillation (AF) recurrence and Sarcoplasmic Endoplasmic Reticulum Calcium ATPase (SERCA) levels in patients treated by epicardial thoracoscopic ablation for persistent AF. Background: Reduced levels of SERCA have been reported in the peripheral blood cells of patients with AF. We hypothesize that SERCA levels can predict the response to epicardial ablation. Methods: We designed a prospective, multicenter observational study to recruit, from October 2014 to June 2016, patients with persistent AF receiving an epicardial thoracoscopic pulmonary vein isolation. Results: We enrolled 27 patients; responders patients (n=15) did not present AF recurrence after epicardial ablation at 1-year follow-up. These patients displayed a marked remodeling of the left atrium, with a significant reduction of inflammatory cytokines, B type Natriuretic Peptide (BNP), and over expression of SERCA as compared to baseline and to non-responders (p<0.05). Furthermore, mean AF duration (HR 1.235 [1.037-1.471], p<0.05), LAV (HR 1.755 [1.126-2.738], p<0.05), BNP (HR 1.945 [1.895-1.999], p<0.05), and SERCA (HR 1.763 [1.167-2.663], p<0.05) were predictive of AF recurrence. Conclusions: Our data indicate that baseline values of SERCA in patients with persistent AF might be predictive of failure to epicardial ablative approach. Intriguingly, epicardial ablation was associated with increased levels of SERCA in responders. Therefore, SERCA might be an innovative therapeutic target to improve the response to epicardial ablative treatments.

Many redox diseases, including diabetes, are associated with an imbalance of calcium homeostasis, regulated mainly by a Ca2+-ATPase pump (SERCA). Dysfunction of this enzyme may be prevented by natural polyphenolic compounds, representing a possible supporting treatment. Compounds that increase SERCA activity/expression may be useful for the treatment of diabetic complications. Stimulation of SERCA1 activity was analyzed experimentally and by molecular modeling. SERCA1 activity under methylglyoxal- and palmitate-induced oxidative stress was evaluated. The viability of INS-1E cells and insulin secretion were determined. [6]-Gingerol, resveratrol, and ellagic acid increased SERCA1 activity and exerted a protective effect under oxidative stress in the noncellular system. We found for the first time that the binding of polyphenols ([6]-gingerol, resveratrol, ellagic acid) to Glu439 in the SERCA1 P-domain may be critical for the stimulation of its activity. Moreover, this binding may also be important in the protective effects against oxidative stress. Direct stimulation of SERCA1 activity by ellagic acid was observed for the first time. In INS-1E cells, these compounds increased insulin secretion.

Low efficiency of in vivo transfection of a few fibers revealed a novel tissue network which temporally amplified growth stimulation in the entire regenerating rat soleus muscle. This acupuncture-like effect was demonstrated when the fibers began to grow after complete fiber degradation, synchronous inflammation, myoblast and myotube formation. The first detection of neonatal sarcoplasmic/endoplasmic reticulum ATPase (SERCA1b) has been made in this system. The neonatal, fast and slow SERCA isoforms displayed consequent change with innervation and differentiation, recapitulating events in muscle development. In vivo transfection of myotubes with plasmids expressing dominant negative Ras or a calcineurin inhibitor peptide (Cain/cabin) proved that the expression of the slow myosin heavy chain and the slow muscle type SERCA2a are dif-ferently regulated. In vivo transfection of a few nuclei of myotubes with dnRas or SER-CA1b shRNA stimulated fiber size growth in the whole regenerating muscle but only until the full size had been reached. Growth stimulation by Ras and SERCA1b antisense was abolished in co-transfection with Cain or in case of perimuscular injection with IL4 antibody. This revealed a novel signalling network resembling to scale-free networks which, starting from transfected fiber myonuclei as “hubs”, can amplify growth stimula-tion uniformly in the entire regenerating muscle.

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0-30 minutes) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA 3 regulated store, given the observation of increased Ca2+ release inducible by low dose tBHQ. Intriguingly, longer-term (&gt;12 hours) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools, yet decreased Ca2+ release responses from tBHQ-sensitive SERCA 3 pool. Our results reveal differential effects of CDN1163 on Ca2+ stores regulated by distinct SERCA isoforms, prompting the need for careful interpretation of the compound’s effects, particularly in cells expressing multiple SERCA isoforms.