Decreased WNT/beta-catenin signalling contributes to the pathogenesis of dilated cardiomyopathy caused by mutations in the lamin a/C gene

摘要

Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is characterized by cardiac conduction abnormalities and left ventricular systolic dysfunction predisposing to heart failure. Previous cardiac transcriptional profiling of Lmna(H222P/H222P) mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/beta-catenin signalling. We confirmed decreased WNT/beta-catenin signalling in the hearts of these mice by demonstrating decreased beta-catenin and WNT proteins. This was correlated with increased expression of soluble Frizzled-related proteins that modulate the WNT/beta-catenin signalling pathway. Hearts of Lmna(H222P/H222P) mice also demonstrated lowered expression of the gap junction connexin 43. Activation of WNT/beta-catenin activity with 6-bromoindirubin-3'-oxime improved cardiac contractility and ameliorated intraventricular conduction defects in Lmna(H222P/H222P) mice, which was associated with increased expression of myocardial connexin 43. These results indicate that decreased WNT/beta-catenin contributes to the pathophysiology of LMNA cardiomyopathy and that drugs activating b-catenin may be beneficial in affected individuals.