Abstract
Desmin is one of five major intermediate filament proteins in cardiomyocytes. Desmin contributes to the maintenance of healthy muscle. The desmin content in cardiomyocytes directly affects the long-term prognosis of patients with heart failure, and lack of desmin leads to myocyte contractile dysfunction. However, the mechanism is elusive. In this study, we measured desmin expression using western blotting and qPCR in the failed hearts of human patients and rats. Our results showed that desmin content was reduced at the protein level in failed hearts and isolated cardiomyocytes. The association of desmin and the gap junction proteins connexin 43 (Cx43) and zonula occludens-1 (ZO-1) was also investigated. Immunoprecipitation assay showed that desmin was associated with Cx43 in cardiomyocytes. To compare the electrical integration of skeletal myoblasts in cocultures with cardiac myocytes, familial amyloid polyneuropathy (FAP) activation rate was found in 33% desmin overexpressing skeletal myoblasts. Desmin not only affected Cx43 and ZO-1 expression but also facilitated the complex of Cx43 and ZO-1 in skeletal myoblasts, which enhanced cell-to-cell electrical coupling of skeletal myoblasts with cardiac myocytes. Desmin has potential as a novel therapeutic target for heart failure. Preservation of desmin may attenuate heart failure.
Highlights
Chronic heart failure (HF) has high morbidity and mortality that is strongly determined by the high propensity of remodeled hearts to have fatal ventricular tachyarrhythmias [1]. e cardiac remodeling process is governed by structural and electrical changes in impulse conductions such as a change in electrical coupling due to abnormal expression of intermediate filament (IF) and connexin 43 (Cx43) constituted gap junctions [2, 3].Desmin is one of five major IF proteins in cardiomyocytes and forms a cytoskeletal network that connects actin filaments with Z-disk and regulates sarcomere architecture. rough its connection to the sarcomere, desmin connects the contractile apparatus to the cardiomyocyte nucleus and mitochondria
Cardiomyocytes lacking the IF protein desmin have numerous mitochondrial structural abnormalities such as disturbed localization, extensive proliferation, sub-sarcolemmal aggregation, swelling, and matrix disorganization that are involved in cardiomyocyte hypertrophy and chamber dilation, resulting in cardiomyopathy and heart failure [6,7,8,9,10]. e mechanism by which desmin IFs contribute to the maintenance of healthy muscle and the mechanism by which lack of desmin leads to cardiomyopathy remain unclear
Cx43, N-cadherin, and zonula occludens-1 (ZO-1) expression was downregulated in HF tissues (p < 0.05) (Figure 1(a))
Summary
Chronic heart failure (HF) has high morbidity and mortality that is strongly determined by the high propensity of remodeled hearts to have fatal ventricular tachyarrhythmias [1]. e cardiac remodeling process is governed by structural and electrical changes in impulse conductions such as a change in electrical coupling due to abnormal expression of intermediate filament (IF) and connexin 43 (Cx43) constituted gap junctions [2, 3]. E cardiac remodeling process is governed by structural and electrical changes in impulse conductions such as a change in electrical coupling due to abnormal expression of intermediate filament (IF) and connexin 43 (Cx43) constituted gap junctions [2, 3]. Adherence junctions are a prerequisite for gap junction assembly in cultured cardiomyocytes and mediate intercellular adhesion and via anchoring actin filaments contribute to propagation of the contraction between cardiomyocytes by linking to the actin cytoskeleton and the IF system at desmin [17,18,19]. Expression of a dominant negative N-cadherin in rat cardiomyocytes disrupts gap junction organization at the cell surface. We determined desmin expression in failed hearts and investigated the correlation with the gap junction proteins Cx43 and ZO1
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