Abstract
Introduction: Pressure overload induces cardiac hypertrophy, electrical remodeling due to changes in various channels, and eventually leads to fibrosis, hardening of the heart, left ventricular diastolic dysfunction, and heart failure. Chloride channels (chloride intracellular channels, Clic) are localized in both plasma membranes and intracellular organelles of various cells, and have recently been reported to be associated with atrial fibrosis. In this study, we examined single-cell RNA-seq analysis of cardiomyocytes for changes in Clic using a pressure overload model due to transverse aortic coarctation (TAC). In addition, a similar analysis was performed on ventricular myocytes in dilated cardiomyopathy. Methods: Single ventricular myocytes were collected from the free wall of the left ventricle after TAC by collagenase treatment in the cardiac hypertrophy phase (3 days after TAC, 1 or 2 weeks (W)) and the heart failure phase (4,8W). The expression of various genes in ventricular myocytes was analyzed for single cells by RNA-seq and compared with sham mice. In addition, a similar study was performed from single ventricular myocytes obtained from dilated cardiomyopathy patients and donors. Results: The expression of myosin heavy chain β (Myh7), a fetal gene, was increased by pressure overload, but the expression of BNP and ANP genes was increased along with the expression of adult Myh6. Regarding Clic, Clic1,4 and 5 increased as compared with Sham mice. Clic1, Clic1 and 4 increased from 3d, and at 8W, Clic1, 4, and 5 also increased . The expression level of these Clic genes is associated with the genes associated with fibrosis (Col4a1, 4a2, 6a2, connective tissue growth factor (CTGF), transforming growth factor-beta 2 (TGFβ2). The KEGG pathway analysis using DAVID for genes with significant associations with Clic1,4, and 5 revealed a strong association with activation of Focal adhesion pathway. Single cell RNA-seq analysis of single ventricular myocytes from patients with dilated cardiomyopathy also showed a increase in CLIC4 and 5 genes compared to healthy donors. Conclusions: Single cell RNA of ventricular myocytes -seq analysis revealed the involvement of chloride channel Clic in myocardial fibrosis and structural remodeling in failing hearts.
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