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Review
. 2016 Apr:93:162-74.
doi: 10.1016/j.yjmcc.2015.11.010. Epub 2015 Nov 10.

Integrins and integrin-related proteins in cardiac fibrosis

Chao Chen  1 , Ruixia Li  2 , Robert S Ross  3 , Ana Maria Manso  4
Affiliations
Review

Integrins and integrin-related proteins in cardiac fibrosis

Chao Chen et al. J Mol Cell Cardiol. 2016 Apr.

Abstract

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.

Keywords: Angiotensin; Fibrosis; Integrins; Mechanical stress; Myocardium; Transforming growth factor beta.

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Figures

Figure 1
Figure 1. Integrins and Integrin-related proteins
Integrins shown spanning the cell membrane, connect and aggregate a range of adapter and signaling proteins such as integrin linked kinase (ILK), focal adhesion kinase (FAK), paxillin (Pax), vinculin (Vcl), talin (Tln), Kindlin, PINCH, Parvin, actinin and even actin. This allows both bridging of ECM to the intracellular cytoskeleton, and also allows propagation of signals bidirectionally across the cell membrane.
Figure 2
Figure 2. Model of mechanical activation of latent TGFβ1
TGFβ1 is secreted in a large latent complex (LLC) that consists of TGFβ1 associated with LAP (Latency Associated Peptide), the short latent complex (SLC), and LTBP-1 (Latent TGFβ1 Binding Protein 1). LAP contains the amino acid sequence motif RGD (Arg-Gly-Asp) which serves as a recognition site for several integrins. Actin / myosin-mediated cell contraction force can be transmitted to an RGD binding site in LAP through the αv integrins and induces a putative conformational change that liberates TGFβ1, activating it.
Figure 3
Figure 3. Myofibroblast precursors and integrin subtypes involved in end-effector regulation
Myofibroblasts can be derived from resident fibroblasts and pericytes, as well as from smooth muscle cells (SMC), endothelial cells (EC), epithelial cells and fibrocytes. As one example, in response to angiotensin II (Ang II), transforming growth factor beta-1 (TGFβ1), can increase the conversion of fibroblasts to myofibroblasts. Mechanical stress (perhaps functioning through Ang II) and ED-A fibronectin (ED-A FN) can also increase this transformation. Integrins are thus involved in TGFβ activation, in EMT regulation and in Ang II synthesis. Myofibroblasts are characterized by the presence of α-smooth muscle actin (α-SMA), stress fibers and collagen production. EMT (epithelial - mesenchymal transition); EndMT (endothelial - mesenchymal transition). + denotes factors can positively increase the transformation of fibroblasts to myofibroblasts.
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