Integrins: Novel Therapeutic Targets for Cardiovascular Diseases

Abstract

Integrins are the principle mediators of molecular dialog between a cell and its extracellular matrix environment. The unique combinations of integrin subunits determine which extracellular matrix molecules are recognized by a cell. Recent studies have demonstrated that remodeling in heart and vasculature is linked to alterations in extracellular matrix and integrin expression. The roles of integrins in controlling cellular behavior have made these molecules highly attractive drug targets. New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation and cardiac growth suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures such as cardiac transplantation. Therapeutic candidates include antibodies, cyclic peptides, peptidomimetics and small molecules. The integrin inhibitors Integrilin and ReoPro have been approved as blood thinners in cardiovascular disease, and newer agents are undergoing testing. Although integrin function is important in the cardiovascular system, there are wide gaps in knowledge. 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 molecules in the cardiovascular system.

Stretch-induced MAP kinase activation in cardiac myocytes: Differential regulation through β1-integrin and focal adhesion kinase

“…Although the AT 1 receptor was blocked in experiments, mechanical stretch may have stimulated the release of another humoral factor, such as endothelin-1 [49] and VEGF [50], which are known to rapidly activate FAK in NRVM [33]. Also, mechanosensing systems, such as stretch-activated channels, cytoskeletal elements could activate FAK [51].…”

Uremic Conditions Drive Human Monocytes to Pro-Atherogenic Differentiation via an Angiotensin-Dependent Mechanism

“…Expression and induction of these molecules has been consistently observed in the initial steps of atherosclerosis and in atherosclerotic plaques [50], [51]. Disruption or antibody-mediated blockage of these molecular targets proved to exert beneficial effects on atherogenesis [52], [53].…”

Sequestosome1/p62: A regulator of redox-sensitive voltage-activated potassium channels, arterial remodeling, inflammation, and neurite outgrowth

“…Both integrins and K v 1.3 channels have recently been targeted for treatment of cardiovascular diseases [103,104,125]. PKCζ is also involved in the integrin-and K v 1.3-mediated signaling pathways, since collagen attachment of cells activates PKCζ, leading to activation of NF-κB and upregulation of α2-integrin in dermal fibroblasts [126,127].…”