Abstract

Cardiac fibroblasts (CFs) play a crucial role in the structural and functional remodeling of the heart, particularly in the development of fibrosis, a condition that can ultimately lead to heart failure. Understanding the signaling pathways that regulate CF proliferation and autophagy is essential for uncovering the mechanisms driving cardiac remodeling. Among these pathways, AMP-activated protein kinase (AMPK) has emerged as a key regulator. This study aimed to elucidate the role of AMPK in catecholamine-induced autophagy and ERKdependent proliferation of CFs. Cells were stimulated with isoproterenol (ISO), norepinephrine (NE), and cAMP analogs. Levels of cAMP, autophagy markers (LC3-II), and phosphorylation of AMPK, AKT, and S6K, along with [3H]-thymidine incorporation as a marker of proliferation, were assessed. The involvement of AMPK in these processes was investigated using the AMPK inhibitor Compound C (CC) and compared with ERK inhibition. Our findings demonstrate that catecholamines increase cAMP levels in CFs, activating AMPK via PKA and inducing autophagy through an mTOR-dependent mechanism. AMPK activation was also crucial for catecholamine-induced ERK-dependent CF proliferation. Inhibition of AMPK with CC blocked both autophagy and proliferation, underscoring AMPK’s central role in these processes. These results provide new insights into the interplay between AMPK-mediated autophagy and ERK-dependent cell proliferation, highlighting potential therapeutic targets for heart failure management.