The antagonistic effects and mechanisms of microRNA-26a action in hypertensive vascular remodelling.

Abstract

BACKGROUND AND PURPOSE:

Hypertensive vascular remodelling is responsible for end-organ damage and is the result of increased extracellular matrix accumulation and excessive vascular smooth muscle cell (VSMC) proliferation. MicroRNA-26a (miR-26a), a non-coding small RNA, is involved in several cardiovascular diseases. We aimed to validate the effect and mechanisms of miR-26a in hypertensive vascular remodelling.

EXPERIMENTAL APPROACH:

Male spontaneously hypertensive rats (SHRs) were injected intravenously with recombinant adeno-associated virus-miR-26a. Samples of thoracic aorta were examined histologically with H&E staining. In vitro, angiotensin II (AngII)-induced VSMCs cultured from thoracic aortae of female Sprague-Dawley rats, were transfected with miR-26a mimic or inhibitor. Western blots, qRT-PCR and immunohistological methods were used, along with chromatin-immunoprecipitation and luciferase reporter assays. Specific siRNAs were used to silence Smad production in VSMCs KEY RESULTS: Levels of miR-26a were lower in the thoracic aorta and plasma of SHRs than in WKY rats. Overexpression of miR-26a inhibited extracellular matrix deposition by targeting connective tissue growth factor (CTGF) and decreased VSMC proliferation by regulating the enhancer of zeste homologue 2 (EZH2)/p21 pathway both in vitro and in vivo. AngII-mediated Smad3 activation suppressed miR-26a expression, which in turn promoted Smad3 activation via targeted regulation of Smad4, leading to further down-regulation of miR-26a.

CONCLUSION AND IMPLICATIONS:

Our data show that AngII stimulated a Smads/miR-26a positive feedback loop, which further reduced expression of miR-26a, leading to collagen production and VSMC proliferation and consequently vascular remodelling. MiR-26a has an antagonistic effect on hypertensive vascular remodelling and can be a strategy for treating hypertensive vascular remodelling.

• Authors: Wenqian Zhang, Qiaozhu Wang, Xin Xing, Lijun Yang, Min Xu, Chunhui Cao, Rong Wang, Weicheng Li, Xiaolin Niu, Dengfeng Gao
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 178 Issue 5 Pg. 1037-1054 (03 2021) ISSN: 1476-5381 [Electronic] England
• PMID: 33305374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The British Pharmacological Society.

Chemical References

• MIRN26 microRNA, rat
• MicroRNAs

Topics

• Animals
• Cell Proliferation
• Female
• Male
• MicroRNAs
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Rats, Sprague-Dawley
• Vascular Remodeling