The Role of Macrophages in the Infarcted Myocardium: Orchestrators of ECM Remodeling

Abstract

Myocardial infarction is the most common form of acute cardiac injury attributing to heart failure. While there have been significant advances in current therapies, mortality and morbidity remain high. Emphasis on inflammation and extracellular matrix remodeling as key pathological factors has brought to light new potential therapeutic targets including macrophages which are central players in the inflammatory response following myocardial infarction. Blood derived and tissue resident macrophages exhibit both a pro- and anti-inflammatory phenotype, essential for removing injured tissue and facilitating repair, respectively. Sustained activation of pro-inflammatory macrophages evokes extensive remodeling of cardiac tissue through secretion of matrix proteases and activation of myofibroblasts. As the heart continues to employ methods of remodeling and repair, a destructive cycle prevails ultimately leading to deterioration of cardiac function and heart failure. This review summarizes not only the traditionally accepted role of macrophages in the heart but also recent advances that have deepened our understanding and appreciation of this dynamic cell. We discuss the role of macrophages in normal and maladaptive matrix remodeling, as well as studies to date which have aimed to target the inflammatory response in combatting excessive matrix deposition and subsequent heart failure.

TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats

“…Tumor necrosis factor-alpha is a multifunctional cytokine that has pleiotropic effects in the cardiovascular system. It is primarily produced by lymphocytes and macrophages; however, various other cell types such as cardiomyocytes, resident cardiac macrophages and vascular smooth muscle cells are also capable of TNF-α production 19 . It acts as a mediator in local homeostasis by regulating cellular growth, cytoprotection, and innate immunity when produced as a part of a physiologic adaptive response.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Overwhelming evidence has associated chronic inflammation with various pathological conditions and their potential causes, including atherosclerosis, cardiovascular events, cancer, autoimmune diseases, metabolic disorders, neurological diseases, and aging (Johnston et al 1987;Gisterå and Hansson 2017;Tabas and Lichtman 2017;de Vries and Quax 2018;Gomez et al 2018;Aday and Ridker 2019;Bercovici et al 2019;Di Benedetto et al 2019;Guner and Kim 2019;Horwitz et al 2019;O'Rourke et al 2019;Othman et al 2019;Trott and Fadel 2019). Many investigations have focused on the major role of macrophages in such contexts and mechanisms for their proinflammatory activation (Murray and Wynn 2011;Wynn and Vannella 2016;Gisterå and Hansson 2017;Tabas and Lichtman 2017;Decano and Aikawa 2018;Funes et al 2018;Swirski and Nahrendorf 2018;O'Rourke et al 2019). Various signal-transduction pathways participate in macrophage activation, which are often regulated by PTMs such as phosphorylation and acetylation (Tietzel and Mosser 2002;Park et al 2011;Zhou et al 2014;Nakano et al 2016;Vergadi et al 2017;Dean et al 2019).…”

IL10 Alters Peri-Collateral Macrophage Polarization and Hind-Limb Reperfusion in Mice after Femoral Artery Ligation

“…They do, however, highlight the potential role played by M2 macrophages with regard to VSMC differentiation and adventitial restructuring to accommodate the growing collateral vessel. M2 macrophages induced by IL10 secrete high levels of TGFb1, known to stimulate VSMC differentiation and extracellular matrix (ECM) deposition [15,19,20]. They also produce high levels of MMP9 [21], which along with MMP2 was significantly increased in the adventitia of growing coronary collateral vessels [22].…”