The antagonistic effects and mechanisms of microRNA-26a action in
hypertensive vascular remodeling
Background and Purpose: Hypertensive vascular remodeling (VR) 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 multiple cardiovascular diseases. We aimed to
validate the effect and mechanisms of miR-26a in hypertensive VR.
Experimental Approach: Spontaneously hypertensive rats (SHRs) were
injected intravenously with recombinant adeno-associated virus-miR-26a.
In vitro experiments, angiotensin II (AngII)-induced VSMCs were
transfected with miR-26a mimic or inhibitor. Key Results: We found
miR-26a downregulated in the thoracic aorta and plasma of SHRs.
Overexpression of miR-26a inhibited extracellular matrix deposition by
targeting connective tissue growth factor (CTGF) and mitigated VSMC
proliferation by regulating the enhancer of zeste homolog 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 downregulation of
miR-26a. Conclusion and Implications: Our study reveals that AngII
stimulates a Smads/miR-26a positive feedback loop, which further reduces
miR-26a expression, leading to collagen production and VSMC
proliferation and consequently, VR. MiR-26a has an antagonistic effect
on hypertensive VR and can be a strategy for treating hypertensive VR.