Abstract
AimsThe Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.Methods and resultsMice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb postnatally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.ConclusionThis study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.
Highlights
Heart disease is a life-threatening and complex multifactorial disease, with both genetic and environmental risk factors contributing to the onset and progression of the disease
This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction
Since we previously identified an important role for Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) during cardiac development we investigated both isoforms of CHAP (S1 Fig) in an in vivo model of experimental heart failure
Summary
Heart disease is a life-threatening and complex multifactorial disease, with both genetic and environmental risk factors contributing to the onset and progression of the disease. Pathological cardiac hypertrophy is initially a compensatory mechanism in response to stressful conditions such as cardiomyocyte loss or increased pressure overload, eventually it leads to impaired cardiac function and progression to heart failure [1,2,3]. In addition to the adaptive hypertrophic response of the heart, cardiac hypertrophy can be caused by intrinsic genetic defects, affecting sarcomeric and cytoskeletal proteins directly, such as in hypertrophic and dilated cardiomyopathy (HCM and DCM). Most genes produce multiple isoforms of mRNAs by alternative splicing or the use of alternative transcription start sites. These are important mechanisms for generating a variety of proteins with distinct functions from a single gene. It is unknown to what extent the misregulated isoform expression of a single gene can contribute to heart disease
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