CCN2 plays a key role in extracellular matrix gene expression in severe hypertrophic cardiomyopathy and heart failure

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• 作者：Tatiana Tsoutsman ; Xiaoyu Wang ; Kendra Garchow ; Bruce Riser ; Stephen Twigg ; Christopher Semsarian
• 关键词：CM ; cardiomyocytes ; CCN2 ; connective tissue growth factor (CTGF) ; ECM ; extracellular matrix ; HCM ; hypertrophic cardiomyopathy ; NM ; non-myocytes ; NTG ; non-transgenic ; NVCM ; neonatal ventricular cardiomyocytes
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：62
• 期：Complete
• 页码：164-178
• 全文大小：2977 K

文摘

Hypertrophic cardiomyopathy (HCM) is the most common inherited primary myocardial disorder. HCM is characterized by interstitial fibrosis and excessive accumulation of extracellular matrix (ECM) proteins. Fibrosis in HCM has been associated with impaired cardiac function and heart failure, and has been considered a key substrate for ventricular arrhythmias and sudden death. The molecular triggers underpinning ECM production are not well established. We have previously developed a double-mutant mouse model of HCM that recapitulates the phenotype seen in humans with multiple mutations, including earlier onset of the disease, progression to a dilated phenotype, severe heart failure and premature mortality. The present study investigated the expression of ECM-encoding genes in severe HCM and heart failure. Significant upregulation of structural m>Fn1m>, regulatory m>Mmp14m>, m>Timp1m>, m>Serpin3Am>, m>SerpinE1m>, m>SerpineE2m>, m>Tgf¦Â1m>, and m>Tgf¦Â2m>; and matricellular m>Ccn2m>, m>Postnm>, m>Spp1m>, m>Thbs1m>, m>Thbs4m>, and m>Tncm> was evident from the early, pre-phenotype stage. Non-myocytes expressed ECM genes at higher levels than cardiomyocytes in normal and diseased hearts. Synchronous increase of secreted CCN2 and TIMP1 plasma levels and decrease of MMP3 levels were observed in end-stage disease. CCN2 protein expression was increased from early disease in double-mutant hearts and played an important role in ECM responses. It was a powerful modulator of ECM regulatory (m>Timp1m> and m>SerpinE1m>) and matricellular protein-encoding (m>Spp1m>, m>Thbs1m>, m>Thbs4m> and m>Tncm>) gene expression in cardiomyocytes when added exogenously m>in vitrom>. Modulation of CCN2 (CTGF, connective tissue growth factor) and associated early ECM changes may represent a new therapeutic target in the treatment and prevention of heart failure in HCM.