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

Abstract

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 LmnaH222P/H222P mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/β-catenin signalling. We confirmed decreased WNT/β-catenin signalling in the hearts of these mice by demonstrating decreased β-catenin and WNT proteins. This was correlated with increased expression of soluble Frizzled-related proteins that modulate the WNT/β-catenin signalling pathway. Hearts of LmnaH222P/H222P mice also demonstrated lowered expression of the gap junction connexin 43. Activation of WNT/β-catenin activity with 6-bromoindirubin-3'-oxime improved cardiac contractility and ameliorated intraventricular conduction defects in LmnaH222P/H222P mice, which was associated with increased expression of myocardial connexin 43. These results indicate that decreased WNT/β-catenin contributes to the pathophysiology of LMNA cardiomyopathy and that drugs activating β-catenin may be beneficial in affected individuals.

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

“…Several groups have documented downregulation and/or abnormal localization and/or activity of connexins (known as gap junction remodeling) in experimental and human cardiomyopathies, including those induced by mutations in LMNA [9][10][11], which seems to predispose to cardiac conduction alterations. The expression of CX43 is modulated by diverse intracellular signaling pathways that can be impaired by the presence of LMNA mutation [11].…”

“…The expression of CX43 is modulated by diverse intracellular signaling pathways that can be impaired by the presence of LMNA mutation [11]. Recently, Le Dour and collaborators showed that hearts of Lmna H222P/H222P mice have reduced WNT and β-catenin expression levels, being this latter less able to interact, on one hand, with the gene encoding CX43 to maintain its transcription and, on the other hand, with CX43 as part of a complex with the intercalated disc [9]. Here, we found that CX43 expression level and conduction defects were improved by drug-induced activation of the WNT/β-catenin signaling pathway.…”

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

“…The first and better described pathway starts from activation of Erk 1/2 signaling leading to a profibrotic process, which encompasses TGFbeta 2-dependent activation of connective tissue growth factor [7,8]. The pathogenicity of Erk 1/2 activation has been proven in preclinical models.…”

“…Mechanosignalling is particularly relevant in conduction tissue, which deserves better investigation. In this respect, it is worth mentioning that reduced connexin 43 amount at the intercalated disks and altered disk morphology are linked to defects in Wnt/betaCatenin signaling in laminopathic heart [8]. …”

“…Further studies will better define the complex molecular mechanism leading to cardiolaminopathies and confirm Erk ½ [9], mTOR [11], TGFbeta 2 [16] betaCatenin [8] or connective tissue growth factor [7] as targets of therapeutic intervention.…”