Defensin-chemokine heteromeric complexes derived from heterocellular activation—a possible target to inhibit CCL5 in cardiovascular settings

Abstract

Submitted Oct 11, 2016. Accepted for publication Oct 17, 2016Oct 17, . doi: 10.21037/atm.2016 View this article at: http://dx.doi.org/10. 21037/atm.2016.11.46 Ischemic heart disease is one of the leading causes of death all over the world even after several medical technologies such as revascularization therapy including catheter intervention and surgery, and drug treatment have been developed. Among them, acute myocardial infarction (AMI) is caused by sudden occlusion of coronary arteries induced by atherosclerotic plaque rapture or vasospasm. Consequently, cardiomyocytes downstream of the culprit site are exposed to hypoxia and eventually die, which induces acute pump failure, fatal arrhythmia, acute valvular dysfunction, cardiac rupture and so on. Even after surviving this acute period, pathological cardiac remodeling changes left ventricular size, mass and function, and leads to several chronic complications such as heart failure and ventricular arrhythmia, which finally increases the mortality. Therefore, development of new treatment strategy for this lifethreatening disease is required.Hypoxia due to marked reduction of blood supply impairs barrier function of endothelial cells. As a result, vessel permeability is enhanced and leukocyte infiltration through vessel walls is subsequently augmented (1,2). Injured or dead cells and damaged extracellular matrix due to prolonged hypoxia release danger associated molecular patterns (DAMPs) which activate innate immune system to release inflammatory mediators such as cytokines, chemokines and adhesive molecules via pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and subsequently recruit immune cells into the infarcted site (2,3). DAMPs also activate the complement cascade which induces further chemotaxis (2,4). Recovery of blood flow during this period induces reperfusion injury because the sudden supply of oxygen in this scenario with excess succinate released by damaged cells allows the reverse flow of electrons through complex II of the electron transport chain, succinate dehydrogenase, such that reactive oxygen species (ROS) are generated in excess (5). This ROS production amplifies tissue damage and additional activation of the complement pathway (1,2).When blood supply to the tissue is markedly reduced, neutrophils are initially recruited into the ischemic zone. They release proteolytic enzymes and more ROS to perpetuate local cytotoxicity. They also secrete further inflammatory mediators and induce subsequent monocyte migration into the ischemic site (2,3,6,7). Humans and mice have at least two monocyte subsets. One is the classical inflammatory monocyte which is typically identified as CD14 + CD16 − monocyte in humans and as Ly6C high monocytes in mice (which like human monocytes are CD14 + CD16 − (8). The other subset is the non-classical inflammatory monocyte, which is typically identified as CD14 low CD16 + in humans and Ly6C low monocyte in mice (9). These human and mouse monocyte subsets have gene expression similari...

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

“…In contrast, CCL5 (RANTES), a chemokine involved in ischemia-reperfusion injury and associated with lymphocyte and monocyte recruitment [ 38 , 39 ], was lower in the CPB group in comparison to control. Patient studies in have shown CCL5 concentration decreases during CPB and return to normal values one hour after termination of CPB [ 40 , 41 ].…”