Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Protein Disulfide Isomerase 4 is an Essential Regulator of Endothelial Function and Survival

Shuhan Bu
,
Aman Singh
,
Hien C. Nguyen
ORCID logo ,
Bharatsinai Peddi
,
Kriti Bhatt
,
Naresh Ravendranathan
,
Jefferson C. Frisbee
,
Krishna K. Singh
* ORCID logo
Version 1 : Received: 28 December 2023 / Approved: 28 December 2023 / Online: 28 December 2023 (16:01:42 CET)

A peer-reviewed article of this Preprint also exists.

Bu, S.; Singh, A.; Nguyen, H.C.; Peddi, B.; Bhatt, K.; Ravendranathan, N.; Frisbee, J.C.; Singh, K.K. Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival. Int. J. Mol. Sci. 2024, 25, 3913. Bu, S.; Singh, A.; Nguyen, H.C.; Peddi, B.; Bhatt, K.; Ravendranathan, N.; Frisbee, J.C.; Singh, K.K. Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival. Int. J. Mol. Sci. 2024, 25, 3913.

Abstract

Endothelial function is regulated by a myriad of complex pathways. In our previous study, the expression of miR-378a-3p was shown to inhibit endothelial autophagy and impair endothelial function. However, the mechanism underlying the effect of miR-378a-3p in endothelial cells remains to be elucidated. By employing an in silico approach, Protein Disulfide Isomerase 4 (PDIA-4) was identified as a target of miR-378-3p; however, its’ role in endothelial cells is not known. We here report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cells’ architecture, accompanied with the loss of endothelial markers and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). Loss of PDIA-4 activates TGF-signaling, and inhibition of TGF-signaling inhibits EndMT in PDIA-4 silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate and/or limit autophagy and EndMT in (patho-)physiological conditions.

Keywords

MicroRNA; PDIA‐4; Autophagy; Apoptosis; Endothelial‐to‐mesenchymal transition; Endothelial function; and Cardiovascular diseases

Subject

Biology and Life Sciences, Life Sciences

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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