Abstract
Alterations in myocardial structure and reduced cardiomyocyte adhesions have been previously described in dilated cardiomyopathy (DCM). We studied the transcriptome of cell adhesion molecules in these patients and their relationships with left ventricular (LV) function decay. We also visualized the intercalated disc (ID) structure and organization. The transcriptomic profile of 23 explanted LV samples was analyzed using RNA-sequencing (13 DCM, 10 control [CNT]), focusing on cell adhesion genes. Electron microscopy analysis to visualize ID structural differences and immunohistochemistry experiments of ID proteins was also performed. RT-qPCR and western blot experiments were carried out on ID components. We found 29 differentially expressed genes, most of all, constituents of the ID structure. We found that the expression of GJA3, DSP and CTNNA3 was directly associated with LV ejection fraction (r = 0.741, P = 0.004; r = 0.674, P = 0.011 and r = 0.565, P = 0.044, respectively), LV systolic (P = 0.003, P = 0.003, P = 0.028, respectively) and diastolic dimensions (P = 0.006, P = 0.001, P = 0.025, respectively). Electron microscopy micrographs showed a reduced ID convolution index and immunogold labeling of connexin 46 (GJA gene), desmoplakin (DSP gene) and catenin α-3 (CTNNA3 gene) proteins in DCM patients. Moreover, we observed that protein and mRNA levels analyzed by RT-qPCR of these ID components were diminished in DCM group. In conclusion, we report significant gene and protein expression changes and found that the ID components GJA3, DSP and CTNNA3 were highly related to LV function. Microscopic observations indicated that ID is structurally compromised in these patients. These findings give new data for understanding the ventricular depression that characterizes DCM, opening new therapeutic perspectives for these critically diseased patients.
Highlights
Dilated cardiomyopathy (DCM), one of the most frequent causes of heart failure (HF), is characterized by ventricular dysfunction, impaired myocardial contractility, abnormal wall thickness, and cardiac chambers dilation [1, 2]
We found that the connexin gene GJA3, the desmosomal gene DSP and the catenin gene CTNNA3 were all significantly and directly related to the EF (r = 0.741, P = 0.004; r = 0.674, P = 0.011 and r = 0.565, P = 0.044, respectively) (Fig 2A, 2D and 2G)
RNA-sequencing analysis allowed us to examine the differences in gene expression between the groups in greater detail, focusing on cell adhesion related genes, category that has been highly enhanced by the functional enrichment analysis performed
Summary
Dilated cardiomyopathy (DCM), one of the most frequent causes of heart failure (HF), is characterized by ventricular dysfunction, impaired myocardial contractility, abnormal wall thickness, and cardiac chambers dilation [1, 2]. The intercalated disc (ID) structure includes cell adhesion molecules that form cell junctions allowing contraction coupling of cardiomyocytes, as well as ensuring the electrical and mechanical connection between cardiac fibers [5]. Some studies have linked genetic alterations in desmosomal genes to cardiomyopathies; desmoplakin (DSP gene) mutations have been implicated in DCM [7]. Alpha catenins are found at high levels in myocardial tissues and contribute to this strong cell-cell adhesion; in patients with DCM and other cardiomyopathies, mutations in these genes have been detected on screening [9]. The important role of some connexins in diseased myocardium is known, such as studies analyzing connexin 43 alterations in HF [11, 12], but other connexin genes remain to be studied in DCM
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