beta 1 -Integrin Receptors and Ligands. Based on their association in heterodimers, the integrin family can be divided in the beta 1 , alpha V and beta 2 subgroups. beta 1 and alpha V members are ubiquitously expressed; the beta 2 subgroup is selectively expressed in leukocytes. Bars connecting alpha and beta subunits indicate known heterodimers. Ligands for each integrin 

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... are heterodimeric cell-surface molecules, which act as the principle mediators of molecular dialog between a cell and its extracellular matrix environment. In addition to their structural functions, integrins mediate signaling from the extracellular space into the cell through integrin-associated signaling and adaptor molecules such as FAK (focal adhesion kinase), ILK (integrin-linked kinase), PINCH (particularly interesting new cysteine-histidine rich protein) and Nck2 (non-catalytic (region of) tyrosine kinase adaptor protein- 2). Via these molecules, integrin signaling tightly and cooperatively interacts with receptor tyrosine kinases (RTKs) signaling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In the heart and blood vessels, the function and regulation of these molecules can be partially disturbed and thus contribute to cardiovascular diseases such as cardiac hypertrophy and atherosclerosis. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these systems (1). Integrins are a superfamily of heterodimeric cell surface receptors involved in cell–cell and cell–matrix adhesion (2). In addition to providing a direct link between the extracellular matrix (ECM) and cytoskeleton, integrins also regulate the production of second messengers within the cell. As multi-functional molecules, integrins are involved in organogenesis, anchoring of stem cells to niches, regulation of gene expression, cell proliferation, differentiation, migration and death (2-8). An important function of integrins is the ability to convert mechanical forces into biochemical signals (7, 9-18). Because dysregulation of integrins is involved in the pathogenesis of several disease states including atherosclerosis and cardiac hypertrophy (5, 19), extensive efforts have been directed toward understanding how integrins couple to signal transduction systems and integrate with other receptor systems. Cell adhesion molecules of the integrin family consist of 18 alpha and 8 beta subunits, which form 24 known alpha-beta-heterodimers depending on cell type and cellular function. Each integrin subunit has a large extracellular, a short transmembrane and small intracellular domain with a total of >1600 amino acids. Integrins are the main receptors for extracellular matrix proteins like collagen, fibronectin and laminin (Figure 1). The alpha subunit generally confers ligand specificity (20, 21) and the beta subunit is important for interacting with the cytoplasmic environment. Cell–matrix interaction via integrins is essential for embryonic development, as well as proliferation, survival, adhesion, differentiation and migration of cells. Ligand binding to the extracellular integrin domain induces conformational changes and integrin clustering for activation of signaling cascades and recruitment of multiprotein complexes to focal adhesions (3, 9). Integrins transmit signals through a variety of intracellular protein kinases and adaptor molecules such as ILK, FAK, talin, paxillin, parvins, p130Cas, Src-family kinases and GTPases of the Rho family. Several integrin subunits like alpha 1, alpha 5 , beta 1 and beta 3 have been directly implicated in the cardiac pathophysiology, however, the underlying molecular mechanism and downstream signaling cascades are poorly understood (22- 25) (Table 1). In the cardiovascular system, integrins are expressed in cardiac myocytes and fibroblasts as well as cells composing the vasculature, blood and neurons. The importance of integrin regulation and function in cardiac cells is given in the following sections. Integrin function is required for proper cardiac development and myocyte attachment to extracellular matrix, growth and viability (26). Integrin-dependent pathways also mediate hypertrophic responses to mechanical stimuli associated with cardiac myocyte strain (10, 11) and are required for stimulation of hypertrophy by phenylephrine (PE) or endothelin-1 (ET-1) (27-29). Cardiac myocytes express integrins alpha 1 , alpha 3 , alpha 5 , alpha 6 , alpha 7 , alpha 9 , alpha 10 , beta 1 , beta 3 , and beta 5 (7), many of which are regulated by developmental and pathological stimuli (30, 31). Adult myocytes express the laminin binding alpha 7 beta 1 heterodimer as the major integrin, while the alpha 5 beta 1 fibronectin receptor and the alpha 6 beta 1 laminin receptor are expressed in cardiac myocytes during embryonic development (32, 33). The primary beta integrin subunit found in myocytes is beta 1 . Different splice variants are expressed in the embryonic (beta 1A ) and adult myocytes (beta 1D ) (34), which differ in specific amino acid sequences at the cytoplasmic domain and their interaction with cytoskeletal and signaling molecules (35). The interaction of cardiac fibroblasts with the surrounding matrix is critical for repair mechanisms, including synthesis of matrix proteins, proliferation, collagen gel contraction and cell motility (36, 37). Cardiac fibroblast activation in the failing heart is associated with increased expression of extracellular matrix proteins (38- 41). Cardiac fibroblasts express integrins alpha , alpha , alpha 3 , alpha 5 , alpha 8 , alpha 10 , beta 1 , beta 3 and beta 5 (37, 42-45). Angiotensin II (Ang II) and other growth factors stimulate cardiac fibroblast contraction and adhesion via beta 1 and alpha v beta 3 integrins, which involve inside-to- outside signaling mechanisms (37, 43-45). The term “integrin” was coined to reflect the capacity of a receptor family to integrate the extracellular and intracellular environment by bidirectional signaling (Hynes, 1987 #496). Interactions with extracellular matrix (ECM), cytoskeletal and various signal transduction cascades enables integrins to mediate both outside in and inside-out signaling (2, 7, 46). Inside-out signaling occurs when specific intracellular signals impinge on integrin cytoplasmic domains, triggering changes in conformation and ligand-binding affinity in the extracellular domain. For example Ang II induces a significant increase in β 1 integrin-dependent adhesion of cardiac fibroblasts to collagen I (37), by inducing a high-affinity state in the integrin molecule. In turn, binding of extracellular ligands produces intracellular signals (ie, outside-in signals) such as changes in intracellular signaling events and cytoskeletal reorganization that critically influence cell shape, migration, growth, and survival (Hynes, 2002 #1). There is number of excellent full reviews dedicated to basic mechanism of integrin bidirectional signaling (2, 47, 48). The specificity of integrin signaling is made possible by alpha and beta subunits that form the heterodimeric pair. Analysis of the amino acid sequences of cytoplasmic tails reveals considerable diversity among integrin subunits (49), suggesting differences in signal transduction among these ECM receptors. Because integrins lack enzymatic activity, activation of signal factors requires interaction with cellular proteins that have kinase activity. The cytoplasmic tail of the beta subunit directly binds to several cytoskeletal proteins that associate with signaling molecules (50). Integrins signal through a wide array of intracellular second messenger systems including calcium channels, phosphatidylinositol-4,5-bisphosphate, phospholipase-C (PLC), the Na/H antiporter, tyrosine and serine/threonine kinases, phosphatases, Rho GTPases, mitogen-activated protein (MAP) kinases, and cyclin D1 (13, 51-57). In blood vessels and cardiac cells, shear stress and stretch are important activators of integrins and signal transduction pathways. Mechanical load applied to integrin ligands (ECM) triggers the assembly and growth of focal contacts (58, 59) and activation of FAK and MAP kinases (18, 60). Although integrins works as “receptors” inducing multiple biological functions, the transduction processes are poorly understood. Stretch-induced conformational changes in the ECM may alter integrin structure, resulting in activation of liganded integrin receptors and focal contact-associated secondary messenger pathways in the cell, such as FAK, Src family kinases, Abl and ILK (50, 61). However, other mechanisms may be operational. For example, membrane-bound proteins such as the ADAMs (a disintegrin and a metalloproteinase domain) also support integrin-mediated cell adhesion since these molecules can cleave ECM proteins by their metalloproteinase domains (62). In addition, mechanical stimulation increases growth factor shedding into the ECM (63). Because ADAMs have the ability to shed many cell-adhesion molecules and cell- surface proteins including cytokines and growth factors, signaling pathways activated by these factors could interact with those of integrins. Integrin signaling may also crosstalk with signals generated by stretch-induced secretion of autocrine factors. Uniaxial stretch stimulates autocrine release of Ang II and ET-1, which induce cellular hypertrophy via phosphorylation cascades (64, 65). Interestingly, AT 1 mediates cardiac hypertrophy by upregulation of beta 1 integrin expression (66) and acts as a mechanoreceptor in cardiac tissue (67). A considerable amount of integrin signaling involves lipid domains located on the cell surface. These microenvironments function as signal organizing centers and platforms by exploiting multiple protein–lipid and protein–protein interactions to link the cytoplasmic tail of transmembrane receptors with other protein scaffolds. These interactions serve to assemble kinases, phosphatases, and other catalytically active molecules in order to generate specific signals that are temporally and spatially controlled (68-70). Integrins signal through at least two types ...