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.

Keywords: collagen; extracellular matrix; fibroblasts; heart failure; inflammation.

Figure 1. The cellular effectors of ECM remodeling in the pressure-overloaded heart.

Mechanical stress triggers transduction of mechanosensitive signaling cascades, activates TGF-β and stimulates neurohumoral mediator release (such as angiotensin, aldosterone and norepinephrine). Fibroblasts are the main effectors of ECM expansion, producing both structural and matricellular ECM proteins. Activated myofibroblasts in the pressure-overloaded heart predominantly originate from local resident fibroblasts, other interstitial cells, such as cardiac pericytes, may also undergo myofibroblast conversion (blue arrows). Other cell types (such as endothelial cells) appear to have very limited direct contributions to the myofibroblast population in the remodeling myocardium. Cardiomyocytes, immune cells and vascular cells are important regulators of ECM remodeling. Mechanical stress triggers synthesis of pro-inflammatory mediators in cardiomyocytes, promoting recruitment of lymphocytes and macrophages. Activated endothelial cells also participate in recruitment of immune cells. Macrophages and lymphocytes may promote fibroblast activation by secreting growth factors (such as TGF-βs). All myocardial cells are capable of producing proteases, involved in ECM remodeling.

Figure 2. The link between immune cell infiltration and ECM expansion in the pressure-overloaded heart.

Serial sections from a mouse heart undergoing transverse aortic constriction for 7 days stained with hematoxylin+eosin (H&E), the macrophage marker Mac2 and Sirius red (to label collagen fibers) show periadventitial infiltration with abundant macrophages in areas of perivascular fibrosis (arrows). Original data and images reported in our published work.

Figure 3. Expression and actions of TSP-1 in failing hearts.

In a mouse model of cardiac pressure overload induced through transverse aortic constriction, TSP-1 immunoreactivity is localized predominantly in perivascular and interstitial areas (data from our published work). TSP-1 overexpression in the pressure-overloaded heart may modulate inflammation, fibrosis and matrix metabolism through several distinct molecular pathways. First, TSP-1 plays an important role in TGF-β activation by binding to the Latency-associated peptide (LAP), thus triggering release of bioactive TGF-β. Second, TSP-1 may inhibit MMP activation, promoting matrix preservation. Third, TSP-1 may exert angiostatic actions. Fourth, TSP-1 may exert anti-inflammatory actions through effects on lymphocytes and macrophages. Fifth, TSP-1 may inhibit NO production and signaling.

Figure 4. Expression and function of the matricellular protein tenascin-C in the failing heart.

A-B: Tenascin-C immunoreactivity is localized in the interstitial and perivascular areas in a mouse model of cardiac pressure overload induced through transverse aortic constriction. Images from our own published work. Tenascin-C may be produced by cardiomyocytes, myofibroblasts and leukocytes in response to mechanical stress or neurohumoral activation. When bound to the interstitial ECM, tenascin-C may exert fibrogenic actions by directly stimulating synthesis of ECM proteins by fibroblasts, or by activating macrophages through integrin or TLR-dependent mechanisms. Effects of tenascin-C on cardiomyocytes remain understudied.

Figure 5. Sustained pressure overload triggers progressive left ventricular dilation and systolic dysfunction through changes in the protease/antiprotease balance.

In the early phase, mechanical stress induces a matrix-preserving fibroblast phenotype inducing collagen synthesis and production of antiproteases (such as TIMPs). Accentuated ECM deposition increases myocardial stiffness causing diastolic dysfunction. Prolonged pressure over load may be associated with transition of infiltrating fibroblasts to a matrix-degrading phenotype that produces matrix metalloproteinases (MMPs), thus causing ECM degradation and generating matrix fragments (matrikines). Matrikines may cause systolic dysfunction by promoting cardiomyocyte apoptosis and by inducing inflammation. Moreover, degradation of the ECM network may deprive cardiomyocytes from matrix-dependent signals required for preservation of function.

Figure 6. The enigmatic basis of ECM degradation in the volume-overloaded heart.

Experimental evidence suggests that cardiac volume overload is associated with a matrix-degrading fibroblast phenotype and with high levels of interstitial MMPs. Immune cells (macrophages and mast cells) may contribute to the proteolytic environment by secreting MMPs. Persistent ECM degradation may trigger cardiomyocyte apoptosis and/or dysfunction and may be responsible for the dilation and systolic dysfunction typically observed in volume-overloaded hearts. The molecular links between mechanical stretch induced by volume overload and the selective activation of proteolytic pathways remain unknown.