BMAL1–SIRT1 Axis Regulates Proliferation, Migration, and Apoptosis in Cardiac Fibroblasts

Background Cardiac remodeling following myocardial injury is tightly regulated by cardiac fibroblast (CF) behavior, including proliferation, migration, and survival. Emerging evidence suggests that circadian-associated transcriptional programs play important roles in cardiovascular homeostasis; however, their functions in CF biology remain poorly defined. Given the reported regulatory relationship between the circadian transcription factor BMAL1 and the metabolic regulator SIRT1, this study aimed to investigate whether BMAL1 modulates CF function through transcriptional regulation of SIRT1. Methods Mouse cardiac fibroblasts were subjected to gain- and loss-of-function manipulation of BMAL1 using plasmid overexpression and shRNA-mediated knockdown. Sirt1 promoter activity was assessed using dual-luciferase reporter assays. CF proliferation, migration, and apoptosis were evaluated using CCK-8 assays, Transwell migration assays, and Annexin V/PI flow cytometry. Pharmacological modulation of SIRT1 activity was performed using the SIRT1 activator resveratrol and the selective inhibitor EX527. Results BMAL1 overexpression significantly enhanced Sirt1 promoter activity in cardiac fibroblasts (P < 0.001), whereas BMAL1 knockdown suppressed it. Functionally, BMAL1 promoted CF proliferation and migration and suppressed apoptosis. These effects were markedly attenuated by SIRT1 inhibition with EX527. Conversely, activation of SIRT1 with resveratrol partially rescued the impaired proliferation, migration, and survival observed in BMAL1-deficient fibroblasts (P < 0.05). Conclusion BMAL1 regulates fundamental cardiac fibroblast behaviors through a SIRT1-dependent transcriptional mechanism. These findings provide mechanistic insight into how circadian-associated transcriptional regulation may influence cardiac remodeling.