The prevention and management of myocardial ischemia/reperfusion (MI/R) injury is an essential part of coronary heart disease surgery and is becoming a major clinical problem in the treatment of ischemic heart disease. Previous studies by our group have demonstrated that pigment epithelium-derived factor (PEDF) improves cardiac function in rats with acute myocardial infarction and reduces hypoxia-induced cell injury. However, the protective function and mechanisms underlying the effect of PEDF in MI/R injury remain to be fully understood. In the present study, the positive effect of PEDF in MI/R injury was confirmed by construction of the adult Sprague-Dawley rat MI/R model. PEDF reduced myocardial infarct size and downregulated cardiomyocyte apoptosis in the I/R myocardium in this model. In addition, PEDF improved cardiac function and increased cardiac functional reserve in rats subjected to MI/R Injury. To further study the protective effect of PEDF and the underlying mechanisms in MI/R injury, a H9c2 cardiomyocyte hypoxia/reoxygenation (H/R) model was constructed. PEDF was confirmed to decrease H/R-induced apoptosis in H9c2 cells, and this anti-apoptotic function was abolished by pigment epithelium-derived factor-receptor (PEDF R) small interfering (si)RNA. Furthermore, administration of PEDF decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in H/R H9c2 cells. Compared with the H/R group, PEDF decreased mitochondrial ROS, increased the mitochondrial DNA copy number, reduced xanthine oxidase and NADPH oxidase activity, as well as RAC family small GTPase 1 protein expression. However, these effects of PEDF were markedly attenuated by PEDF-R siRNA. To the best of our knowledge, the present study is the first to identify the protective effect of PEDF in MI/R injury, and confirm that the antioxidative effect PEDF occurred via inhibition of ROS generation via PEDF-R under MI/R conditions.

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Both decreased autophagy positive regulator AMP activated protein kinase (AMPK) level and promoted mitophagy are observed in oxygen‐glucose deprivation (OGD) cardiomyocytes treated with pigment epithelium‐derived factor (PEDF). This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Our previous study reveals that PEDF increases the protein kinase Cα (PKCα) and phospho‐PKCα (p‐PKCα) contents to promote mitophagy. Thus, we investigated the association between PKCα and mitophagy. Here we identify an interaction between PKCα and Unc‐51‐like kinase 1 (ULK1), essential component of mitophagy. Further analyses show this is a direct interaction within a domain of ULK1 that termed the serine/threonine‐rich domain (S/T domain). Notably, a deletion mutant ULK1 that lacks the binding domain is defective in mediating PEDF‐induced mitophagy. Furthermore, we demonstrate that ULK1 is phosphorylated at Ser317/555/777 and Raptor is also phosphorylated by phospho‐PKCα. Phospho‐ULK1 (p‐ULK1) at these sites are all essential for PEDF‐induced mitophagy and reduce the release of mitochondrial ROS and DNA. This study therefore identifies a previously uncharacterized interaction between the ULK1 and PKCα that can replace the AMPK‐dependent mitophagy processes.

Background We occasionally noticed that native collateral blood flow showed a recessive trend in the early stages of acute myocardial infarction in rats, which greatly interferes with the accurate assessment of native collateral circulation levels. Here, we sought to recognize the coronary collateral circulation system in depth, especially the microcirculation part, on this basis. Methods and Results In this study, we detected native collateral flow with positron emission tomography perfusion imaging in rats and found that the native flow is relatively abundant when it is initially recruited. However, this flow is extremely unstable in the early stage of acute myocardial infarction and quickly fails. We used tracers to mark the collateral in an ischemic area and a massive preformed collateral network was labeled. The ultrastructures of these collateral microvessels are flawed, which contributes to extensive leakage and consequent interstitial edema in the ischemic region. Conclusions An unrecognized short‐lived native coronary collateral microcirculation reserve is widely distributed in rat hearts. Recession of collateral blood flow transported by coronary collateral microcirculation reserve contributes to instability of native collateral blood flow in the early stage of acute myocardial infarction. The immature structure determines that these microvessels are short‐lived and provide conditions for the development of early interstitial edema in acute myocardial infarction.