SENP1 protects against myocardial ischaemia/reperfusion injury via a HIF1α-dependent pathway

AIMS: SUMO-specific protease 1 (SENP1) removes SUMO from proteins and plays important roles in the regulation of multiple cellular signalling pathways. However, little is known about the role of SENP1 in coronary heart disease. In this study, we tested the hypothesis that SENP1 protects against myocardial ischaemia/reperfusion (I/R) injury and investigated the underlying molecular mechanisms involved. METHODS AND RESULTS: First, we found that SENP1 levels increased after I/R in human and mouse myocardium in vivo and in rat cardiomyocytes in vitro. We then performed coronary artery ligation to induce I/R injury in wild-type (WT) and heterozygous SENP1-knockdown (SENP1(+/-)) mice. Compared with WT mice, SENP1(+/-) mice had normal cardiac function at baseline but lower systolic function after I/R. Post-I/R myocardial infarction sizes were larger in SENP1(+/-) mice. Furthermore, we demonstrated that SENP1 regulates the expression of hypoxia-inducible factor 1 α (HIF1α), a critical protective factor during I/R, in vivo and in vitro. Overexpression of HIF1α reversed the deteriorating effect of SENP1 knockdown on cellular death. CONCLUSION: Our results suggest that SENP1 deficiency exacerbates I/R injury in cardiomyocytes via a HIF1α-dependent pathway.