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.

Protective Effect of CXCR4 Antagonist DBPR807 against Ischemia-Reperfusion Injury in a Rat and Porcine Model of Myocardial Infarction: Potential Adjunctive Therapy for Percutaneous Coronary Intervention

“…Interestingly, during the preparation of the manuscript, there was a report by Zhang, et al [ 42 ], stating that when a vascular leakage blocker, known as CU06-1004, was delivered before reperfusion in a single high dose in rats, it could significantly protect vascular integrity and improve cardiac function by suppressing reperfusion-induced inflammation. Moreover, no in vivo efficacy was observed when the repetitive low-dose treatment was adopted for CU06-1004.…”

CU06‐1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium

“…CU06-1004 that was developed as an endothelial dysfunction blocker was reported to protect the endothelium from multiple endothelial permeability mediators including VEGF, histamine, and IL1β through the cAMP/Rac/cortactin pathway. 14 In addition, the efficacy [15][16][17][18][19][20] However, the effect of CU06-1004 on HAE is yet unknown. CU06-1004 has shown efficacy in protecting endothelial integrity against such diverse stimulators that involve different signaling but eventually lead to endothelial barrier disruption.…”

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

“…The ischemia caused by an intracoronary thrombus leads to profound hypoxia, inflammation, and edema 2 , and although many organs can tolerate mild to moderate edema, even small increases in interstitial fluid volume can significantly compromise cardiac function 3 . The fundamental cause of edema is an increase in vascular permeability, and some evidence suggests that cardiac function can be improved via the administration of vascular-leakage blockers, which inhibit both cardiac microvascular endothelial cell (CMVEC) hyperpermeability and the infiltration of circulating neutrophils 4 . Nevertheless, the mechanisms that regulate cardiac microvascular permeability have rarely been investigated as potential targets for the treatment of ischemic myocardial disease.…”