Involvement of microRNA-146a-5p, but not -155-5p and -29b-5p, in left ventricular remodeling and dysfunction in spontaneously hypertensive rats

Abstract

The contribution of microRNAs remains poorly understood in the context of hypertensive cardiac pathology. The role of miR-146a-5p, miR-155-5p, and miR-29b-5p in cardiac hypertrophy and dysfunction was investigated in spontaneously hypertensive rats (SHRs). Seven-month-old SHR (n = 7 male, n = 9 female) and normotensive Wistar Kyoto rats (WKY; n = 7 male, n = 9 female) underwent echocardiography. Plasma concentrations of inflammatory markers were measured by ELISA. Interstitial and perivascular fibrosis and percentage macrophage infiltration were determined by histology. Left ventricular (LV) mRNA expressions of cardiac remodeling markers and miRNA expressions were determined by RT-PCR. Circulating vascular cell adhesion molecule-1 (VCAM-1), macrophage infiltration, interstitial and perivascular fibrosis, relative wall thickness (RWT), early diastolic mitral inflow to tissue lengthening velocity at lateral mitral annulus (E/e'), and LV mRNA expression of NFKBIA and SOD2 were greater in SHRs. MidFS, e', and a' were lower in SHRs. Expression of LOX1, Col1a/Col3a ratio, circulating c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and RWT were greater in females. No difference in miR-29b-5p expression was noted. MiR-155-5p expression was lower in female and associated with stroke volume and absolute heart and LV masses. MiR-146a-5p expression was greater in SHRs and associated with systolic blood pressure (SBP), circulating VCAM-1, macrophage infiltration, interstitial fibrosis, normalized heart and LV masses, RWT, and a'. MiR-146a-5p was also associated with circulating VCAM-1 after adjustments for SBP. In addition, greater expression of miRNA-146a-5p reversed the relationship between circulating VCAM-1 and macrophage infiltration. Changes in the expression of miR-155-5p may be involved with a cardiac phenotype related to sexual dimorphism. Conversely, upregulation of miR-146a-5p expression may act as a countermechanism induced by myocardial inflammation in the setting of reactive fibrosis, established LV hypertrophy, and impaired diastolic function.NEW & NOTEWORTHY We investigated roles of microRNAs-146a-5p, -155-5p, and -29b-5p in development of cardiac hypertrophy and dysfunction in SHRs. We showed that miR-146a-5p expression was upregulated in SHRs and positively associated with indices of concentric LVH and diastolic dysfunction, potentially as countermechanism in response to myocardial inflammation, whereas miR-155-5p was expressed in a manner consistent with sexual dimorphism. Our data may offer novel insights on involvement of miRNAs in myocardial inflammation in hypertension-induced cardiac hypertrophy and dysfunction.

Keywords: cardiac dysfunction; fibrosis; hypertension; inflammation; microRNAs.