Short-Chain Acyl-CoA Dehydrogenase as a Therapeutic Target for Cardiac Fibrosis

Cardiac fibrosis is considered as unbalanced extracellular matrix production and degradation, contributing to heart failure. Short-chain acyl-CoA dehydrogenase (SCAD) negatively regulates pathological cardiac hypertrophy. The purpose of this study was to investigate the possible role of SCAD in cardiac fibrosis. In vivo experiments were performed on spontaneously hypertensive rats (SHR) and SCAD-knockout mice. The cardiac tissues of hypertensive patients with cardiac fibrosis were used for the measurement of SCAD expression. In vitro experiments, with angiotensin II (Ang II), SCAD siRNA and adenovirus-SCAD were performed using cardiac fibroblasts (CFs). SCAD expression was significantly decreased in the left ventricles of SHR. Notably, swim training ameliorated cardiac fibrosis in SHR in association with the elevation of SCAD. The decrease in SCAD protein and mRNA expression levels in SHR CFs were in accordance with those in the left ventricular myocardium of SHR. In addition, SCAD expression was downregulated in CFs treated with Ang II in vitro, and SCAD siRNA interference induced the same changes in cardiac fibrosis as Ang II-treated CFs, while adenovirus-SCAD treatment significantly reduced the Ang II-induced CFs proliferation, alpha smooth muscle actin (α-SMA), and collagen expression. In SHR infected with adenovirus-SCAD, the cardiac fibrosis of the left ventricle was significantly decreased. However, cardiac fibrosis occurred in conventional SCAD-knockout mice. SCAD immunofluorescence intensity of cardiac tissue in hypertensive patients with cardiac fibrosis was lower than that of healthy subjects. Altogether, the current experimental outcomes indicate that SCAD has a negative regulatory effect on cardiac fibrosis and support its potential therapeutic target for suppressing cardiac fibrosis.