Critical Role of Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 in the Pathogenesis of Ischemic Cardiomyopathy

Abstract

Background-Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. Methods and Results-Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. Conclusions-Defective

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing

“…The overlapping and distinct activities of mCcl2 and mCcl12 allow subcomponents of the hMCP-1 protein to be dissected. After MI, mCcl2 has been shown to regulate macrophage recruitment and activation (44,45). In addition, cardiac myofibroblasts isolated from WT but not from Ccl2-deleted animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity (45).…”

Oncostatin M Induces FGF23 Expression in Cardiomyocytes

“…Since MCP-1 mediates the recruitment of mononuclear cells and increases in ischemic cardiomyopathy (ICM) [23,24] we wanted to know whether patients with ICM also show increased levels of FGF23. In Figure 3A it can evidently be recognized that this growth factor is present in high quantity in cardiomyocytes of patients with ischemic cardiomyopathy, while in control samples FGF23 is not detectable ( Figure 3A).…”

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

“…Proliferation was determined by bromodeoxyuridine incorporation using a commercially available colorimetric kit (Roche Applied Science) as previously described (21). To normalize data from different experiments, proliferation in response to 5% serum was expressed as fold increase to cells maintained in serum-free medium.…”