Inhibition of Bif-1 confers cardio-protection in myocardial infarction

Myocardial infarction (MI) remains a major cause of chronic heart failure. Endoplasmic reticulum (ER) stress is an emerging therapeutic strategy to prevent adverse remodeling of the infarcted heart. However, little is known about how Bax-interacting protein 1 (Bif-1), a member of the endophilin B family, is involved in mediating cardiac ER stress in ischemic heart disease. Here, a combination of a left anterior descending coronary artery ligation mouse model and an adenovirus-based transfection strategy was used to investigate the effect of Bif-1 on cardiac remodeling and function after MI. 4-Phenylbutyric acid (4-PBA) was used to understand the role of ER stress in cardiac remodeling. To discover the molecular mechanism, an RNA sequencing study was performed. We found that Bif-1 expression was highly elevated in the heart infarct border zone post-MI and neonatal rat cardiomyocytes treated with oxygen and glucose deprivation. Adenovirus-based knockdown of Bif-1 protected the heart from MI as demonstrated by attenuated maladaptive remodeling and preserved contractile function. ER stress inhibition by 4-PBA alleviated the adverse effects of Bif-1 overexpression on cardiac structure and function. Furthermore, we explored the underlying mechanism by RNA sequencing and identified Bif-1 as a molecule involved in cardiac lipid metabolism. In conclusion, our study identifies Bif-1 as a negative regulator of cardiac protection in MI. Inhibition of Bif-1 alleviates ER stress, which may restore lipid metabolism homeostasis to preserve cardiac function post-MI. Therefore, Bif-1 is a potential novel therapeutic target for ischemic heart disease.<b>NEW & NOTEWORTHY</b> Our study demonstrated that Bif-1 contributes to adverse cardiac remodeling and dysfunction following MI by promoting ER stress. Pharmacological inhibition of ER stress ameliorates cardiac remodeling and dysfunction. In addition, we identified Bif-1 as a negative regulator of cardiac lipid metabolism post-MI, as shown by elevated expression of Acox1, Pla2g7, Acsbg1, Acsl5, Ch25h, and Bcat1 in the heart. These findings suggest that Bif-1 plays a crucial role in cardiac decline post-MI.