Dissecting the Role of the Extracellular Matrix in Heart Disease: Lessons from the Drosophila Genetic Model

Abstract

The extracellular matrix (ECM) is a dynamic scaffold within organs and tissues that enables cell morphogenesis and provides structural support. Changes in the composition and organisation of the cardiac ECM are required for normal development. Congenital and age-related cardiac diseases can arise from mis-regulation of structural ECM proteins (Collagen, Laminin) or their receptors (Integrin). Key regulators of ECM turnover include matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs). MMP expression is increased in mice, pigs, and dogs with cardiomyopathy. The complexity and longevity of vertebrate animals makes a short-lived, genetically tractable model organism, such as Drosophila melanogaster, an attractive candidate for study. We survey ECM macromolecules and their role in heart development and growth, which are conserved between Drosophila and vertebrates, with focus upon the consequences of altered expression or distribution. The Drosophila heart resembles that of vertebrates during early development, and is amenable to in vivo analysis. Experimental manipulation of gene function in a tissue- or temporally-regulated manner can reveal the function of adhesion or ECM genes in the heart. Perturbation of the function of ECM proteins, or of the MMPs that facilitate ECM remodelling, induces cardiomyopathies in Drosophila, including cardiodilation, arrhythmia, and cardia bifida, that provide mechanistic insight into cardiac disease in mammals.

Expression of Calcification and Extracellular Matrix Genes in the Cardiovascular System of the Healthy Domestic Sheep (Ovis aries)

“…Other ECM genes that decreased with age included COL1A1 and BGN. The ECM proteases known as matrix metallopeptidases (MMPs) and their tissue inhibitors, TIMPs, are important modulators of matrix protein turnover (Elmore et al, 1998;Hughes and Jacobs, 2017). It is thought that alterations of the balance between MMPs and TIMPs are critical in the formation of aortic aneurysms and age-associated physiological changes in the cardiovascular system (Rabkin, 2014;Meschiari et al, 2017).…”

Select Septate Junction Proteins Direct ROS-Mediated Paracrine Regulation of Drosophila Cardiac Function

“…In the myocardium, Kune might be involved in the synchronous contraction of the CMs, a process that could be facilitated by the uniform localization of Kune across the entire CM surface. Alternatively, Kune interaction between the pericardial and cardiac cells might not involve their direct homotypic interaction but rather be mediated by the basement membrane that resides between PCs and CMs, at least in certain regions of the fly heart (Hughes and Jacobs, 2017; Rotstein and Paululat, 2016). In addition, an aberrant change in the pericardial nephrocyte morphology caused by loss of pericardial Kune (Figure 7) might also alter Kune level in the CM.…”

As time flies by: Investigating cardiac aging in the short-lived Drosophila model

“…The matrix proteins help form a structural "scaffold" that supports cell-cell and cell-matrix interactions, whereas the matricellular proteins contribute to the formation of the scaffold but do not integrate into it. ECM regulation in the heart is linked to cardiac output, with disruption or experimental modulation of ECM deposition causing cardiomyopathy in both mammalian and Drosophila models [80].…”