Abstract
Ischemia–reperfusion (I/R) injury accelerates the cardiomyocytes (CMs) death by oxidative stress, and thereby deteriorates cardiac function. There has been a paradigm shift in the therapeutic perspective more towards the prevention or amelioration of damage caused by reperfusion. Cardiac microvascular endothelial cells (CMECs) are more vulnerable to reperfusion injury and play the crucial roles more than CMs in the pathological process of early I/R injury. In this study, we investigate that CU06-1004, as a vascular leakage blocker, can improve cardiac function by inhibiting CMEC’s hyperpermeability and subsequently reducing the neutrophil’s plugging and infiltration in infarcted hearts. CU06-1004 was delivered intravenously 5 min before reperfusion and the rats were randomly divided into three groups: (1) vehicle, (2) low-CU06-1004 (1 mg/kg, twice at 24 h intervals), and (3) high-CU06-1004 (5 mg/kg, once before reperfusion). CU06-1004 treatment reduced necrotic size and cardiac edema by enhancing vascular integrity, as demonstrated by the presence of intact junction proteins on CMECs and surrounding pericytes in early I/R injury. It also decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) on CMECs, resulting in reduced infiltration of neutrophils and macrophages. Echocardiography showed that the CU06-1004 treatment significantly improved cardiac function compared with the vehicle group. Interestingly, single high-dose treatment with CU06-1004 provided a greater functional improvement than repetitive low-dose treatment until 8 weeks post I/R. These findings demonstrate that CU06-1004 enhances vascular integrity and improves cardiac function by preventing lethal myocardial I/R injury. It can provide a promising therapeutic option, as potential adjunctive therapy to current reperfusion strategies.
Highlights
Acute myocardial infarction (AMI) is the leading cause of death and critical disability worldwide[1]
Combined Evans blue and TTC staining was performed 48 h after reperfusion and showed that CU06-1004 treatment significantly reduced the necrotic area in a dose-dependent manner compared with the vehicle, even though the area at risk (AAR), which indicated the ischemic region under LAD artery ligation, was the same in all groups (Fig. 1b–d)
These results suggest that CU06-1004 has cardioprotective effects in preventing lethal myocardial I/R injury, and treatment with a single high-dose administration of CU06-1004 during early myocardial I/R injury was more effective than repeated low-dose administration of this agent
Summary
Acute myocardial infarction (AMI) is the leading cause of death and critical disability worldwide[1]. The standard therapy, which consists of timely myocardial reperfusion using primary percutaneous coronary intervention (PCI), has been considered the most effective therapeutic strategy in patients with AMI2. Reperfusion of the occluded culprit arteries within a short time can reduce ischemic injury and prevent necrosis of cardiomyocytes (CMs). Several pieces of evidence have shown that reperfusion of the ischemic myocardium causes further damage, accounting for up to 50% of the final infarct size. Despite a significant amount of research as well as encouraging preclinical results with multiple agents, most of the clinical trials to prevent ischemia–reperfusion (I/R) injury have been disappointing[4,5,6,7,8,9]; it is important to identify and develop therapies that potentially reduce infarct size
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