Cardiac matrix: a clue for future therapy

Abstract

Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.

Keywords: APT; Angiogenesis; CPC; CSC; CVD; DNA methyl transferase; DNMT; ECM; Heart; MMP; MicroRNA; ROS; SERCA; Stem cell; TIMP; VEGF; acute pulmonary thromboembolism; cardiac progenitor cell; cardiac stem cell; cardiovascular disease; extracellular matrix; matrix metalloproteinase; miRNA; reactive oxygen species; sarco endoplasmic reticulum ca(2+)ATPase; tissue inhibitor of MMP; vascular endothelial growth factor.

Figure 1

Pressure and/volume overload, diabetes, homocysteine and renin-angiotensin- aldosterone system (RAAS) engendered oxidative stress that activates latent MMPs and imbalances MMP/TIMP axis (remodeling). This generates angiogenic and anti-angiogenic factors, leading to compensatory to de-compensatory congestive heart failure (CHF).

Figure 2

Activation of MMP-9 increases ECM turn over, attenuates miRNAs, induces cardiac stem cell apoptosis and inhibits their differentiation leading to pathological cardiac remodeling.

Figure 3

Mechanism of pressure overload (ascending aortic banding) mediated compensatory cardiac hypertrophy to de-compensatory heart failure. During early stages of aortic banding, angiogenesis is increased due to up-regulation of MMP-2, vascular endothelial growth factor (VEGF) and inhibition of MMP-9. However, sustained overload results in de-compensatory heart failure due to anti-angiogenesis, where expression of MMP-9 supersedes that of MMP-2 and promotes release of anti-angiogenic factors such as angiostatin, endostatin and parstatin. MMP-9 also stimulate endothelial mesenchymal transition (EndMT) leading to fibrosis and end stage heart failure.

Figure 4

The effect of different vascular endothelial growth factors (VEGF) following their binding to corresponding receptors (VEGFR). VEGF1 and 2 up regulates vasculogenesis and angiogenesis through Flt -1and Flk-1/KDR pathway, whereas VEGF3 enhances lymphangiogenesis through Flt-4 pathway.

Figure 5

The unique cross –talk amongst MMP-9/TIMP4, miRNA, epigenetic modification, fibrosis, hypertrophy, cardiac stem cell proliferation and differentiation, growth factors, autophagy and apoptosis is maintained in the cardiac matrix. The interactions of these molecules alter in pathological remodeling due to change in matrix milieu. Dissecting the causative factor (s) and their interactions will provide a clue to for future therapy.