Abstract 403: MicroRNA-21 Ablation Exacerbates Aldosterone-mediated Cardiac Inflammation, Fibrosis, Hypertrophy and Dysfunction
Excess aldosterone (ALDO) causes hypertension and cardiac hypertrophy, inflammation and fibrosis that lead to cardiac dysfunction. We reported that ALDO/SALT treatment increases left ventricle miR-21 expression after 2 weeks of treatment, and the elevation persists for up to 8 weeks. We aim to study the role of genetic ablation of miR-21 in ALDO/SALT-mediated cardiac inflammation, fibrosis, hypertrophy and function.
Eight-week old uninephrectomized male miR-21 knockout (miR21KO) or wild-type (WT) mice were assigned to 4 groups (N=12/grp): WT-Control, WT-ALDO/SALT, miR21KO-Control and miR21KO-ALDO/SALT. Animals were treated for 8 weeks. ALDO (0.15 μg/h) or vehicle (PEG 300) was administered by osmotic minipump. SALT (1.0% NaCl + 0.3% KCl) was administered in tap water. Cardiac function was determined by echocardiography. Tissues were weighed and standardized to body weight. mRNA levels were quantified by qPCR. Another set of animals (N=12/grp) was implanted with carotid artery catheters for conscious MAP determination.
ALDO/SALT-mediated cardiac dysfunction was exacerbated in miR21KO mice (EF: 38.0 ± 2.0 vs. 43.0 ± 4.1 %, p<0.05) compared with WT mice (EF: 50.0 ± 3.7 vs. 54.7 ± 3.1 %, NS). ALDO/SALT-mediated cardiac hypertrophy was exacerbated in miR21KO mice compared with WT mice (ALDO-SALT/control: 1.30 ± 0.04 vs. 1.18 ± 0.02, p<0.05).
Fibrosis marker connective tissue growth factor (Ctgf) mRNA expression remained elevated by ALDO/SALT only in miR21KO mice (7.22 ± 1.96 fold change vs. control, p<0.05). Similar results were observed with collagen I and fibronectin. Inflammation marker Serpine1 (PAI-1) mRNA expression was upregulated by ALDO/SALT only in miR21KO mice (3.11 ± 0.54 fold change vs. control, p<0.05).
Despite the exacerbation in cardiac dysfunction, hypertrophy, and fibrosis and inflammation markers expression in miR21KO mice, ALDO/SALT raised MAP to similar levels in both strains (WT: 139 ± 9 vs. 106 ± 2 mm Hg, p<0.05; miR21KO: 142 ± 8 vs. 114 ± 4, p< 0.05).
These results show that miR-21 ablation exacerbates ALDO/SALT-mediated cardiac inflammation, fibrosis, hypertrophy and dysfunction independently of blood pressure suggesting that therapies that increase cardiac levels of miR-21 may benefit patients with primary aldosteronism.
Author Disclosures: M. Syed: None. J.P. Ball: None. K.W. Mathis: None. M.E. Hall: None. M.J. Ryan: None. M.E. Rothenberg: None. D.G. Romero: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; NIH grant. B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; AHA grant.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.