Aerobic exercise intervention improves angiotensin Ⅱ-induced cardiac remodeling by inhibiting RBP4-STRA6-Wnt/β-catenin pathway

Abstract

Most cardiovascular diseases are accompanied by cardiac remodeling, but physical exercise can mitigate and decelerate this process. Retinol-binding protein 4 (RBP4) has been associated with cardiovascular disease in both basic research and clinical settings. Therefore, the present study aimed to investigate the mechanism underlying RBP4 in exercise ameliorating cardiac remodeling. Our findings indicate that mice model of angiotensin Ⅱ (Ang Ⅱ)-induced cardiac hypertrophy exhibited elevated blood pressure, impaired cardiac function, increased myocardial fibrosis, and mitochondrial degradation, alongside elevated RBP4 levels in myocardial tissue. A 9-week aerobic exercise regimen improved these indexes and decreased RBP4 expression. The cell surface receptor stimulated by retinoic acid 6 (STRA6), which serves as a membrane receptor for RBP4, is implicated in the activation of the Wnt/β-catenin signaling pathway, with its knockdown potentially inhibiting this pathway. Our subsequent analyses identified a significant upregulation of the STRA6 protein in myocardial tissue of the mice model of cardiac hypertrophy. Further investigations showed that total β-catenin levels remained unchanged, there was an increase in nuclear β-catenin, which enhanced the expression of matrix metalloproteinase 7 (MMP7) and cyclooxygenase 2 (COX2). These alterations were reversed following exercise intervention. The results suggest that RBP4 enhances STRA6 expression in cardiac hypertrophy mice hearts and facilitates β-catenin nuclear translocation and transcriptional activity, leading to elevated levels of MMP7 and COX2 expression. Aerobic exercise appears to attenuate the myocardial inflammatory response by reducing RBP4 expression and inhibiting the Wnt/β-catenin pathway, thereby ameliorating Ang Ⅱ-induced cardiac remodeling.