Novel role of extracellular matrix protein 1 (ECM1) in cardiac aging and myocardial infarction

Abstract

Introduction The prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart. Methods Young adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-β1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells. Results ECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role. Conclusions ECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro . Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis.

Analysis of Secreted Proteins from Prepubertal Ovarian Tissues Exposed In Vitro to Cisplatin and LH

“…The presence of secreted Ahnak, Ecm1, Tpt1, and Ywhaz only in CIS might be linked to the ongoing apoptotic processes in the cultured ovarian tissues at this time but in an opposite way. Ahnak, an unusual desmoyokin scaffolding protein characterized by its large size of approximately 700 kDa [ 35 ], Ecm1, involved in ECM remodeling [ 36 ], and Tpt1, encoded by a p53 target gene, might be released in an attempt to alleviate apoptosis [ 37 , 38 ], whereas Ywhaz, belonging to the 14-3-3 family hub proteins involved in many signal transduction pathways, including apoptosis [ 39 ], could favor this process. Moreover, secreted Fbn2 and Fbln2 known to interact in the formation of elastic fibers were found only in LH, thus indicating an inductive effect by LH, overcome by CIS.…”

The Effect of Shionone on Sepsis-Induced Acute Lung Injury by the ECM1/STAT5/NF-κB Pathway

“…As the extracellular matrix factor, ECM1 controls the expression of the inflammatory lymphocytes in the respiratory system (Rostila et al, 2020). The recombinant ECM1 rapidly guided the Erk1/2 and Akt activation (Hardy et al, 2019). The ECM1 deficiency prevented the pathological progression in inflammatory disease by upregulating Arg1 expression and presenting M2 macrophage phenotype characteristic (Yasen et al, 2021).…”

Airway Remodeling in Asthma

“…As discussed earlier, fibroblasts represent a specialized mesenchymal cell population that produce collagen, fibronectin, and proteoglycans which comprise major components of the ECM and are found in the stroma of virtually all tissue types (216). In response to injury, fibroblasts deposit ECM components providing the physical architecture and matrix-generated signals that promote wound healing (217,218). In age-induced pathologies such as asthma, COPD, and IPF, a reorganization of airway architecture has been consistently observed.…”