Abstract
The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2’s protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/- ) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2 -/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.
Highlights
As the most severe manifestation of coronary artery disease (CAD), acute myocardial infarction (AMI) remains a leading cause of death in the western world despite an overall reduction in AMI mortality due to more aggressive approaches to coronary revascularization [1, 2]
Given the abundance of six-transmembrane protein of the prostate 2 (Stamp2) in leukocytes and its potential anti-inflammatory role in atherosclerosis, we investigated the effects of Stamp2 deficiency on left ventricular (LV) function in a murine model of myocardial ischemia and reperfusion (I/R) injury
We show that Stamp2 deficiency promotes adverse LV structural remodeling after myocardial I/R injury by elevating proinflammatory polymorphonuclear neutrophils (PMN) activation
Summary
As the most severe manifestation of coronary artery disease (CAD), acute myocardial infarction (AMI) remains a leading cause of death in the western world despite an overall reduction in AMI mortality due to more aggressive approaches to coronary revascularization [1, 2]. Revascularization is associated with inflammatory tissue injury at the site of ischemia and reperfusion (I/R) leading to subsequent ventricular fibrotic remodeling and heart failure (HF) [3]. I/R is a major trigger of polymorphonuclear neutrophils (PMN) recruitment and activation. Intriguing data suggest that PMN’s level of inflammatory activation determines the extent of fibrotic scar generation and thereby recovery or persistent deterioration of cardiac function [5,6,7]. Whereas total antibody-mediated depletion of PMN impairs infarct healing [8], targeted and more sophisticated modulation, e.g. by inhibition of neutrophil-secreted inflammatory proteins like myeloperoxidase (MPO), improves cardiac repair and function [9]
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