title: Class A scavenger receptor attenuates myocardial infarction-induced cardiomyocyte necrosis through suppressing M1 macrophage subset polarization.
abstract: Classically (M1) and alternatively (M2) activated macrophage subsets play differential roles in left ventricular remodeling after myocardial infarction (MI). The precise mechanism underlying the regulation of M1/M2 polarization during MI is unknown. We hypothesized that class A scavenger receptor (SR-A), a key modulator of inflammation, may steer macrophage polarization, which in turn influences cardiomyocytes necrosis after MI. MI was induced in wild type (WT) and SR-A deficient (SR-A(-/-)) mice by left anterior descending coronary artery ligation. Cardiac function deterioration, ventricular dilatation and fibrosis were all exacerbated in SR-A(-/-) mice following MI compared to WT littermates. Meanwhile, enhanced M1 macrophage polarization was observed in SR-A(-/-) mice, along with increased production of M1 signature cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) as demonstrated by immunohistochemistry, flow cytometry, quantitative real-time PCR, and ELISA assays. Moreover, activation of the activated apoptosis signal regulating kinase 1 (ASK1)/p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathway was markedly elevated in SR-A(-/-) animals post-MI. Most importantly, transplantation using bone marrow from SR-A(+/+) mice partially restored M1 macrophages and significantly augmented left ventricular fractional shortening in SR-A(-/-) mice. SR-A attenuated MI-induced cardiac remodeling by suppressing macrophage polarization toward a skewed M1 phenotype, reducing secretion of IL-1β, IL-6, and TNF-α, and dampening the ASK1/p38/NF-κB signaling pathway. Therefore, SR-A may exert a protective effect against MI, which may represent a new interventional target for treatment of post-infarct remodeling and subsequent heart failure.
authors.affiliation: Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Hu
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Hui
authors.initials: H
authors.lastname: Bai
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhu
authors.forename: Rongmei
authors.initials: R
authors.lastname: Zhou
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ben
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016764:Cell Polarity; D002469:Cell Separation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D060888:Real-Time Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D051117:Scavenger Receptors, Class A