The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Abstract

The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.

Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression

“…4a (Detailed information was shown in Additional file 3: Table S3). Among the significantly enriched Gene Ontology (GO) Biological Process (BP) pathways, some fibrosis-related terms stood out, such as extracellular matrix (GO: 0031012) (BH adjusted p value = 1.55 × 10 − 15 ) and regulation of blood pressure (BH adjusted p value = 4.10 × 10 − 7 ) [33,34]. To better interpret the results, we constructed a DEG GO term network (Fig.…”

The Non-Fibrillar Side of Fibrosis: Contribution of the Basement Membrane, Proteoglycans, and Glycoproteins to Myocardial Fibrosis

“…Subsequently, hydroxylation and oxidative deamination of collagens by lysyl hydroxylase (PLOD1) and lysyl oxidase (LOX) lead to cross-linking and stabilization of collagen fibers [79,80]. Further post-translational regulation of the collagen fibers is mediated by matricellular proteins, the non-ECM proteins that reside in the interstitial space and play important roles in stabilization of collagen fibers; these include SPARC, osteopontin, and periostin [81,82]. Contribution of the fibrillar ECM to myocardial fibrosis has been extensively reviewed [4,6,83,84] ( Table 2), and as such will not be the main focus of this article.…”

Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

“…Dilated cardiomyopathy (DCM) is one of the most common cardiomyopathy worldwide characterized by left ventricular dilation and decline in contraction function, which is the third leading cause of congestive heart failure [1][2][3]. Recent studies of pathological mechanisms underlying heart failure focus on structural changes in cardiomyocytes and extracellular matrix to explain the deleterious contractile function [4,5]. However, the exact molecular mechanism in the onset and progression of DCM is still unclear.…”