Differences in microRNA-29 and Pro-fibrotic Gene Expression in Mouse and Human Hypertrophic Cardiomyopathy.

Autor: Liu Y; Division of Cardiology, Hypertrophic Cardiomyopathy Center of Excellence, University of California, San Francisco, San Francisco, CA, United States.; Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, United States., Afzal J; Division of Cardiology, Hypertrophic Cardiomyopathy Center of Excellence, University of California, San Francisco, San Francisco, CA, United States.; Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, United States., Vakrou S; Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, United States., Greenland GV; Division of Cardiology, Hypertrophic Cardiomyopathy Center of Excellence, University of California, San Francisco, San Francisco, CA, United States.; Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, United States., Talbot CC Jr; Johns Hopkins School of Medicine, Institute for Basic Biomedical Sciences, Baltimore, MD, United States., Hebl VB; Intermountain Medical Center, Intermountain Heart Institute, Murray, UT, United States., Guan Y; Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, United States., Karmali R; Division of Cardiology, Hypertrophic Cardiomyopathy Center of Excellence, University of California, San Francisco, San Francisco, CA, United States., Tardiff JC; Sarver Heart Center, University of Arizona Health Sciences, Tucson, AZ, United States., Leinwand LA; Molecular, Cellular and Developmental Biology, Biofrontiers Institute, University of Colorado, Boulder, CO, United States., Olgin JE; Division of Cardiology, Hypertrophic Cardiomyopathy Center of Excellence, University of California, San Francisco, San Francisco, CA, United States., Das S; Department of Anesthesia and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States., Fukunaga R; Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, United States., Abraham MR; Division of Cardiology, Hypertrophic Cardiomyopathy Center of Excellence, University of California, San Francisco, San Francisco, CA, United States.; Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, United States.
Jazyk: angličtina
Zdroj: Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2019 Dec 17; Vol. 6, pp. 170. Date of Electronic Publication: 2019 Dec 17 (Print Publication: 2019).
DOI: 10.3389/fcvm.2019.00170
Abstrakt: Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy and fibrosis. Studies in two mouse models (R92W-TnT/R403Q-MyHC) at early HCM stage revealed upregulation of endothelin (ET1) signaling in both mutants, but TGFβ signaling only in TnT mutants. Dysregulation of miR-29 expression has been implicated in cardiac fibrosis. But it is unknown whether expression of miR-29a/b/c and profibrotic genes is commonly regulated in mouse and human HCM. Methods: In order to understand mechanisms underlying fibrosis in HCM, and examine similarities/differences in expression of miR-29a/b/c and several profibrotic genes in mouse and human HCM, we performed parallel studies in rat cardiac myocyte/fibroblast cultures, examined gene expression in two mouse models of ( non-obstructive ) HCM (R92W-TnT, R403Q-MyHC)/controls at early (5 weeks) and established (24 weeks) disease stage, and analyzed publicly available mRNA/miRNA expression data from obstructive -HCM patients undergoing septal myectomy/controls (unused donor hearts). Results: Myocyte cultures: ET1 increased superoxide/H 2 O 2 , stimulated TGFβ expression/secretion, and suppressed miR-29a expression in myocytes. The effect of ET1 on miR-29 and TGFβ expression/secretion was antagonized by N-acetyl-cysteine, a reactive oxygen species scavenger. Fibroblast cultures: ET1 had no effect on pro-fibrotic gene expression in fibroblasts. TGFβ1/TGFβ2 suppressed miR-29a and increased collagen expression, which was abolished by miR-29a overexpression. Mouse and human HCM: Expression of miR-29a/b/c was lower, and TGFB1 /collagen gene expression was higher in TnT mutant-LV at 5 and 24 weeks; no difference was observed in expression of these genes in MyHC mutant-LV and in human myectomy tissue. TGFB2 expression was higher in LV of both mutant mice and human myectomy tissue. ACE2 , a negative regulator of the renin-angiotensin-aldosterone system, was the most upregulated transcript in human myectomy tissue. Pathway analysis predicted upregulation of the anti-hypertrophic/anti-fibrotic liver X receptor/retinoid X receptor (LXR/RXR) pathway only in human myectomy tissue. Conclusions: Our in vitro studies suggest that activation of ET1 signaling in cardiac myocytes increases reactive oxygen species and stimulates TGFβ secretion, which downregulates miR-29a and increases collagen in fibroblasts, thus contributing to fibrosis. Our gene expression studies in mouse and human HCM reveal allele-specific differences in miR-29 family/profibrotic gene expression in mouse HCM, and activation of anti-hypertrophic/anti-fibrotic genes and pathways in human HCM.
(Copyright © 2019 Liu, Afzal, Vakrou, Greenland, Talbot, Hebl, Guan, Karmali, Tardiff, Leinwand, Olgin, Das, Fukunaga and Abraham.)
Databáze: MEDLINE
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