CTRP6-mediated cardiac protection in heart failure via the AMPK/SIRT1/PGC-1α signalling pathway

Heart failure (HF) remains a significant global health concern with limited effective treatments available. C1q/TNF-related protein 6 (CTRP6) is a member of the CTRP family analogous to adiponectin and its role in HF pathogenesis remains unclear. Here, we investigated the impact of CTRP6 on HF progression. To mimic heart failure with reduced ejection fraction (HFrEF), we used isoproterenol injection in mice and administered adenovirus vectors expressing CTRP6 (Ad-CTRP6) via tail vein injection. We assessed cardiac function through echocardiography and histology. CTRP6's effects on hypertrophy, fibrosis, apoptosis, oxidative stress and mitochondrial function were analysed. Downstream pathways (phosphorylated AMP-activated protein kinase (p-AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) were studied in heart tissues. In vitro, isoproterenol-stimulated H9c2 cardiomyocytes were treated with CTRP6 to examine viability, apoptosis, F-actin and signalling proteins. Compound C was used to assess AMPK involvement. CTRP6 expression was lower in the plasma of HF patients. In an isoproterenol-induced HFrEF mouse model, adenovirus-mediated overexpression of CTRP6 ameliorated cardiac dysfunction and reduced cardiomyocyte apoptosis, oxidative stress, inflammation and myocardial injury markers. Mechanistically, CTRP6 activation of the AMPK/SIRT1/PGC-1α signalling pathway restored mitochondrial homeostasis, evidenced by reduced mitochondrial reactive oxygen species levels, increased ATP content, and enhanced mitochondrial complex I/III activities in cardiac tissues. In vitro studies using isoproterenol-stimulated H9c2 cardiomyocytes corroborated these findings, demonstrating that CTRP6 upregulation attenuated hypertrophy, apoptosis, oxidative stress and mitochondrial dysfunction. Furthermore, these effects were partially reversed by the AMPK inhibitor Compound C, implicating the involvement of the AMPK pathway in CTRP6-mediated cardioprotection. CTRP6 alleviates HF progression through the AMPK/SIRT1/PGC-1α signalling pathway.