CircMboat2 activates chaperone-mediated autophagy to promote the reversal of myocardial hypertrophy after pressure unloading of the left ventricle

Abstract Purpose Preoperative left ventricular hypertrophy (LVH), postoperative LVH regression, and medical treatment are closely associated with prognosis in patients with severe aortic valvular stenosis; however, it remains unclear whether the timing of pressure unloading is associated with LVH regression and whether new therapeutic targets for promoting LVH regression can be identified during LVH reversal. Therefore, in this study, we aimed to characterize the effects of early and late unloading on LV remodeling and to identify a novel therapeutic target for promoting LVH regression. Methods In mice subjected to transverse aortic constriction (TAC), different timings of LV unloading were achieved by aortic debanding to simulate aortic valve replacement. Reversal target circMboat2 was identified by circRNA sequencing from early unloading mice and was characterized and functionally validated in mice and phenylephrine-treated neonatal rat cardiomyocytes. The mechanisms by which circMboat2 promotes LVH regression were explored, with a focus on chaperone-mediated autophagy (CMA), by using classical techniques, such as immunoprecipitation and molecular docking. Results Four weeks after early unloading (unloading two weeks after TAC), LVH and myocardial fibrosis were completely reversed, whereas eight weeks after late unloading (unloading six weeks after TAC), only LVH rather than fibrosis was completely reversed. CircMboat2 was significantly upregulated during reversal after unloading, and it inhibited cardiomyocyte hypertrophy in TAC mice and cultured cardiomyocytes. Overexpression of circMboat2 in late unloading mice accelerated LVH reversal. CircMboat2 enhanced CMA in cardiomyocytes by directly binding to the marker lysosomal associated membrane protein 2, leading to the degradation of pyruvate kinase M2 (PKM2). Conclusions Late unloading of pressure overload delays LVH regression and leads to residual fibrosis. CircMboat2 attenuates cardiomyocyte hypertrophy and accelerates LVH regression by enhancing CMA and promoting the degradation of PKM2.Abstract Picture