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Published on: December 2, 2016
Involvement of microRNA-146a-5p, but not -155-5p and -29b-5p, in left ventricular remodeling and dysfunction in
Siluleko A Mkhize1, Sulé Gunter1,2, Ashmeetha Manilall1
1Integrated Molecular Physiology Research Initiative, Department of Physiology, School of Biomedical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
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.
Insights
MicroRNAs miR-146a-5p and miR-155-5p play roles in hypertension-induced cardiac issues. Upregulated miR-146a-5p may counter inflammation, while miR-155-5p shows sex-specific expression patterns in cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Hypertension Research
Background:
- MicroRNA (miRNA) contributions to hypertensive cardiac pathology are not fully understood.
- Specific miRNAs, including miR-146a-5p, miR-155-5p, and miR-29b-5p, are implicated in cardiac hypertrophy and dysfunction.
Purpose of the Study:
- To investigate the roles of miR-146a-5p, miR-155-5p, and miR-29b-5p in the development of cardiac hypertrophy and dysfunction in spontaneously hypertensive rats (SHRs).
- To explore potential sex-specific differences in miRNA expression and their association with cardiac remodeling markers.
Main Methods:
- Echocardiography was performed on 7-month-old SHRs and normotensive Wistar Kyoto rats (WKY).
- Plasma inflammatory markers were quantified using ELISA.
- Cardiac fibrosis, macrophage infiltration, and left ventricular (LV) mRNA and miRNA expressions were analyzed via histology and RT-PCR.
Main Results:
- SHRs exhibited increased vascular cell adhesion molecule-1 (VCAM-1), macrophage infiltration, fibrosis, relative wall thickness (RWT), and LV mRNA expressions of NFKBIA and SOD2, alongside decreased MidFS, e', and a'.
- miR-146a-5p expression was upregulated in SHRs and associated with systolic blood pressure (SBP), VCAM-1, macrophage infiltration, fibrosis, LV mass, RWT, and a'.
- miR-155-5p expression showed sex-specific differences, correlating with stroke volume and cardiac masses, while miR-29b-5p expression remained unchanged.
Conclusions:
- Upregulation of miR-146a-5p may serve as a counter-regulatory mechanism against myocardial inflammation, fibrosis, and diastolic dysfunction in hypertension.
- miR-155-5p expression patterns suggest involvement in sex-dimorphic cardiac phenotypes.
- These findings offer novel insights into the involvement of specific miRNAs in hypertension-induced cardiac hypertrophy and dysfunction.
