STAT3诱导心肌细胞FGFBP1表达驱动病理性心脏重构的分子机制

Abstract

Cardiac remodeling underlies the progression to heart failure, yet the molecular drivers remain incompletely defined. Here, we identify fibroblast growth factor binding protein 1 (FGFBP1) as a previously unrecognized regulator of pathological cardiac remodeling. FGFBP1 expression was markedly increased in hypertrophic human myocardium and in murine hearts exposed to angiotensin II (Ang II) or transverse aortic constriction (TAC). Using FGFBP1 knockout mice, we found that loss of FGFBP1 significantly attenuated Ang II- and TAC-induced cardiac dysfunction, hypertrophy, and interstitial fibrosis. RNA sequencing revealed that FGFBP1 deficiency suppressed fibrogenic and extracellular matrix-associated gene programs in pressure-overloaded hearts. Mechanistically, Ang II activated STAT3 in cardiomyocytes, which in turn induced FGFBP1 transcription and promoted profibrotic signaling. Pharmacological inhibition of STAT3 using S3I-201 reduced FGFBP1 expression and recapitulated the protective effects observed in FGFBP1 KO mice. These findings establish FGFBP1 as a STAT3-dependent effector of pathological remodeling and highlight the STAT3-FGFBP1 axis as a potential therapeutic target.