Tenascin-C May Accelerate Cardiac Fibrosis by Activating Macrophages via the Integrin αVβ3/Nuclear Factor–κB/Interleukin-6 Axis

131

Cardiac fibrosis is one of the major components of the healing mechanism following any injury of the heart and as such may contribute to both systolic and diastolic dysfunction in a range of pathophysiologic conditions. Canonically, it can occur as part of the remodeling process that occurs following myocardial infarction or that follows as a response to pressure overload. Integrins are cell surface receptors which act in both cellular adhesion and signaling. Most importantly, in the context of the continuously contracting myocardium, they are recognized as mechanotransducers. They have been implicated in the development of fibrosis in several organs, including the heart. This review will focus on the involvement of integrins and integrin-related proteins, in cardiac fibrosis, outlining the roles of these proteins in the fibrotic responses in specific cardiac pathologies, discuss some of the common end effectors (Angiotensin II, transforming growth factor beta 1 and mechanical stress) through which integrins function and finally discuss how manipulation of this set of proteins may lead to new treatments which could prove useful to alter the deleterious effects of cardiac fibrosis.

Section: End Effectors Of the Fibrotic Processmentioning

confidence: 99%

“…al. demonstrated that αvβ3 is the functional receptor in macrophages for Tenascin-C, mediating migration and the inflammatory response [120]. In another study, Friedrichs et.…”

Section: End Effectors Of the Fibrotic Processmentioning

confidence: 99%

Integrins and integrin-related proteins in cardiac fibrosis

Chen

Ross

et al. 2016

131

“…TN-C expression is an independent predictor of mortality in patients with dilated cardiomyopathy [121] and serum TN-C levels are a potentially useful predictor of LV remodelling and prognosis after MI [122]. A number of preclinical murine studies have shown that TN-C knockout improves cardiac remodelling and fibrosis after MI [123] or Ang II infusion [124]. TN-C knockout mice also exhibit delayed recruitment of myofibroblasts after MI [125].…”

Section: Modified Ecm Componentsmentioning

confidence: 99%

“…Indeed, TN-C can directly stimulate CF migration and myofibroblast transdifferentiation [125]. In addition to direct effects, TN-C may have indirect effects on CF for example by inducing IL-6 production from macrophages with resultant increased collagen production by CF [124].…”

Section: Modified Ecm Componentsmentioning

confidence: 99%

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

168

124

Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

“…In addition, loss of TNC attenuates inflammation following cardiac fibrosis. TNC interacts with integrins localized on the surface of the macrophage, upregulating IL-6, and FAK-Src through NF-κB and augmenting the inflammatory response [168]. …”

Section: Ecm-cell Interactions In the Injured Myocardiummentioning

confidence: 99%

Extracellular matrix-mediated cellular communication in the heart

Valiente-Alandí

Schafer

Blaxall

2016

135

107

The extracellular matrix (ECM) is a complex and dynamic scaffold that maintains tissue structure and dynamics. However, the view of the ECM as an inert architectural support has been increasingly challenged. The ECM is a vibrant meshwork, a crucial organizer of cellular microenvironments. It plays a direct role in cellular interactions regulating cell growth, survival, spreading, proliferation, differentiation and migration through the intricate relationship among cellular and acellular tissue components. This complex interrelationship preserves cardiac function during homeostasis; however it is also responsible for pathologic remodeling following myocardial injury. Therefore, enhancing our understanding of this cross-talk may provide mechanistic insights into the pathogenesis of heart failure and suggest new approaches to novel, targeted pharmacologic therapies. This review explores the implications of ECM-cell interactions in myocardial cell behavior and cardiac function at baseline and following myocardial injury.