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 (LAD) 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 (NRCMs) treated with oxygen and glucose deprivation (OGD). 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.