MicroRNA‐21 Overexpression Attenuates Aldosterone‐Mediated Cardiac Injury and Hypertension
Authors: Syed Maryam , Ball Jana P , Broome Hanna J , Hall Michael E , Ryan Michael J , Hatley Mark E , Cardozo Licy L Yanes , Romero Damian G 
Published: November 2023

Excess aldosterone (ALDO) causes hypertension and cardiac hypertrophy, inflammation and fibrosis that leads to cardiac dysfunction. We previously reported that ALDO/SALT increases left ventricle (LV) microRNA‐21 (miR‐21) expression, but whether this upregulation is protective, deleterious or a bystander is unknown. Furthermore, we also reported that miR‐21 genetic ablation exacerbates ALDO/SALT‐mediated cardiac and LV hypertrophy, evidenced at the cellular level by an increase in cardiomyocyte cross‐sectional area. Moreover, miR‐21 genetic ablation exacerbates ALDO/SALT‐mediated cardiac fibrosis (Ctgf, Col1a1) and inflammation (PAI‐1, Spp1), and interstitial and perivascular fibrosis, which ultimately lead to an exacerbation in cardiac dysfunction despite no significant change in blood pressure. These results suggest that miR‐21 plays a protective role in ALDO/SALT‐mediated cardiac injury and dysfunction. To test this hypothesis, we performed a follow up study to analyze the effect of increased miR‐21 levels in ALDO/SALT‐mediated cardiac injury and dysfunction. For this study, we used transgenic mice with constitutive, ubiquitous miR‐21 overexpression.

Eight‐week old uninephrectomized male miR‐21 overexpression (miR21OE) or wild‐type littermate (WT) control mice were treated with ALDO (0.15 μg/h) and SALT (1.0 % NaCl + 0.3 % KCl) or vehicle for 2 or 8 weeks (N=8/group). miR21OE mice have a ~30‐fold increase in cardiac miR‐21 expression as quantified by qRT‐PCR. miR‐21 overexpression did not affect ALDO/SALT‐induced cardiac or LV hypertrophy. miR‐21 overexpression attenuated ALDO/SALT‐mediated LV mRNA expression upregulation of the fibrotic markers connective tissue growth factor (Ctgf, 5.3 ± 1.4 vs. 2.1 ± 0.5 FC, p<0.05) and fibronectin 1 (Fn1, 6.1 ± 1.9 vs. 1.9 ± 0.3 FC, p<0.05) after 8 weeks of treatment. However, miR‐21 overexpression did not affect ALDO/SALT‐mediated LV expression of collagen I (Col1a1), collagen III (Col3a1) or lysyl oxidase (Lox). miR‐21 overexpression attenuated ALDO/SALT‐mediated LV mRNA expression upregulation of the inflammation marker osteopontin (Spp1, 6.7 ± 2.5 vs. 2.0 ± 0.8 FC, p<0.05) after 8 weeks of treatment. However, miR‐21 overexpression did not affect ALDO/SALT‐mediated LV expression of plasminogen activator inhibitor type 1 (PAI‐1, Serpine1), tumor necrosis factor (Tnfa), or interleukins IL1β, IL6 or IL12. Furthermore, miR‐21 overexpression did not alter cardiac ALDO/SALT‐mediated mRNA expression regulation of natriuretic peptides A and B (Nppa and Nppb) and myosin heavy chain α and β (Myh6 and Myh7) genes. Moreover, miR‐21 overexpression abolished ALDO/SALT‐mediated increases in blood pressure (142 ± 4 vs. 123 ± 10 mm Hg, WT‐ALDO/SALT vs. miR21OE‐ALDO/SALT, p<0.05) to levels similar to control treated animals (127 ± 3 vs. 129 ± 4 mm Hg, WT‐Control vs. miR21OE‐Control).

Our results suggest that miR‐21 overexpression does not affect ALDO/SALT‐mediated cardiac hypertrophy but partially attenuates cardiac fibrosis and inflammation. These beneficial effects on cardiac injury are associated with a decrease in the ALDO/SALT‐mediated rise in blood pressure. These findings suggest that miR‐21 supplementation therapies may have a beneficial effect to attenuate ALDO‐mediated cardiac injury and hypertension in patients with primary aldosteronism.

Support or Funding Information

Supported by American Heart Association Grant 12SDG8980032 (DGR).