Cyclophilin B deficiency enhances myocardial energy synthesis and protects against heart failure in preclinical models.

Abstract

Heart failure (HF) represents the end stage of cardiovascular diseases with high mortality and limited treatment options. Cyclophilin B (CypB), known mainly as an endoplasmic reticulum chaperone, has been implicated in cardiovascular diseases. But the role of CypB in HF remains unclear. Transverse aortic constriction (TAC) surgery on mice in vivo was conducted to model cardiac hypertrophy (CH) and HF, and angiotensin II (Ang II) was applied to neonatal rat cardiomyocytes in vitro to mimic cardiomyocyte hypertrophy. The effects of CypB deficiency on CH/HF were evaluated by echocardiography, tissue staining, and molecular expression assays. The mechanism of CypB action was elucidated by RNA sequencing, bioinformatics analysis, mitochondrial function assay, immunofluorescence staining, glucose uptake assay, PET/CT scan, transcription factor analysis, dual luciferase reporter assay, Cut&Run-qPCR assay, STAT3 inhibitor, and overexpression virus. Increased expression of CypB has been observed in hypertrophied and failing hearts. CypB deficiency improves cardiac function, reduces hypertrophy after TAC surgery, and attenuates Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CypB deletion increases AMPK phosphorylation, enhances the expression of glucose transporter type 1 (GLUT1), glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and downstream signaling molecules, thereby promoting cardiac glucose catabolism and mitochondrial function. STAT3 transcriptionally activates CypB expression, STAT3 inhibition ameliorates TAC-induced heart failure, and CypB deficiency reverses STAT3 overexpression-induced HF. CypB deficiency ameliorates CH and HF by enhancing cardiac energy production, providing a potential therapeutic target for CH and HF.