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 (E-M) 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 E-M 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.

Reversal of Phospholamban Inhibition of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Using Short, Protein-interacting RNAs and Oligonucleotide Analogs

“…In the heart, miRNAs are involved both in cardiogenesis (14,15) and in disease including: diabetic cardiomyopathy, hypertrophy, ischemia, and electrical remodeling (16 -22). Recent developments in both therapeutic inhibition and enhancement of miRNA function have demonstrated great promise for counteracting cardiac diseases (22,23). However, the off-target effects of miRNAs and antisense oligonucleotides that target miRNAs (i.e.…”

Mitochondrial Transcription Factor A's role in heart failure.

“…Early-stage aortic banding results in inhibition of MMP9, but sustained mechanical overload causes de-compensatory heart failure, leading to increased MMP9 expression and cardiac fibrosis in end-stage heart failure. As aforementioned, activation of MMP9 increases extracellular matrix turnover in the failing heart, 50 resulting in increased apoptotic signaling in pressure overload heart failure (Mishra et al 2013 Fujino et al 2012). Within TFAM over-expression models, it is observed that proteolytic enzyme MMP9 is reduced in MI-induced HF, along with functional morphologies (Ikeuchi et al 2005).…”

“…MMP9 is a distinguishing factor in pathological cardiac remodeling (Mishra et al 2013). This observation correlates with known studies showing that increased activation of MMPs is observed in TFAM ablation and oxidative stress models (Larsson et al 1998;Lamparter and Maisch 2000).…”

“…MMPs are collagenases and MMP9 excessively degrades collagen but in cardiac remodeling collagen turnover is faster than elastin, leading to a stiffening myocardium (Mishra et al 2013). This interplay is a major factor in hypertrophy and heart failure.…”

“…It provides a microenvironment for mechanical, cellular, and molecular activities and is crucial to supporting the physiological myocardium. MMPs and their respective TIMPs (tissue inhibitors of metalloproteinases) regulate matrix degradation, which affects cardiac fibrosis and performance (Mishra et al 2013). …”