CU06-1004 enhances vascular integrity and improves cardiac remodeling by suppressing edema and inflammation in myocardial ischemia–reperfusion injury

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.

Heart attack: Drug boosts survival of heart cells during treatment

A drug that can block excess inflammation and leakage from blood vessels shows promise in boosting the survival of heart cells following treatment for heart attack. Reperfusion therapy aims to restore blood flow around or through blocked arteries after a heart attack. However, in some cases the treatment can trigger the overproduction of reactive oxygen species, damaging the endothelium (lining of blood vessels) and further injuring heart muscle cells. Hun-Jun Park (Catholic University) and Young-Guen Kwon (Yonsei University), both in Seoul, South Korea, and co-workers, have demonstrated that the drug CU06-1004, used successfully in animal trials for other conditions, can enhance cardiac integrity and function following reperfusion in rats. A single high dose of CU06-1004 inhibited leakage from heart microvascular endothelial cells, reducing the build-up of fluid in tissues and limiting tissue death.