The Cardiovascular Actions of Protease-Activated Receptors

Abstract

Protease-activated receptors (PARs) comprise a family of G protein-coupled receptors with a unique proteolytic activation mechanism. PARs are activated by thrombin or other coagulation or inflammatory proteases formed at sites of tissue injury. PARs play a particularly important role in the pathogenesis of clinical disorders characterized by chronic inflammation or smoldering activation of the coagulation cascade. Individual PARs have been linked to the regulation of a broad range of cellular functions. Recent studies identify PAR family members in the vasculature (including within atherosclerotic lesions) and in the heart. Here, PAR-triggered responses contribute to vasoregulation and influence cardiac electrical and mechanical activity. PAR activation also is linked to structural remodeling of the vasculature and the myocardium. This review focuses on the cardiovascular actions of PARs that play a role in normal cardiovascular physiology and that are likely to contribute to cardiovascular diseases.Thrombin was first identified as a trypsin-like serine protease produced at sites of vessel injury or tissue damage, which plays a key role in blood coagulation by converting fibrinogen to fibrin (the fibrous matrix of blood clots). However, early studies exposed an additional effect of thrombin to promote platelet aggregation, even in the absence of any other coagulation factors. The molecular basis for the cellular actions of thrombin, distinct from its role in clot formation, was first elucidated by the Coughlin laboratory with the cloning of PAR-1 in 1991 (Coughlin, 2000). Subsequent research identified PAR-1 as a prototype of a family of related PARs that have important nonhemostatic functions in development, play a role in tumor biology, and orchestrate a series of highly regulated responses that are integral to the inflammatory response and are vital for normal tissue repair. The broad scope of cellular processes regulated by PARs is evident from the recent excellent reviews that consider roles for PARs in inflammation and wound healing, vasoregulation, angiogenesis, atherosclerosis, gastrointestinal disorders, pain perception by sensory neurons, airway hyper-reactivity, and inflammatory pulmonary diseases (Vergnolle, 2000;Macfarlane et al., 2001;Vergnolle et al., 2001;Major et al., 2003;Ossovskaya and Bunnett, 2004). PARs also exert a wide range of cardiovascular actions. Most of the published literature has focused on PAR-mediated action in platelets and the vasculature. Here, PARs are critical for normal hemostasis and contribute to the pathogenesis of vascular disorders characterized by chronic inflammation or smoldering activation of the coagulation cascade (including vascular atherosclerosis). However, there is recent evidence that PARs also exert direct effects on the heart that lead to changes in contractile performance and structural remodeling of ventricular cardiomyocytes. This review briefly summarizes the pharmacological properties of the four known PAR family members before focusing on re...

p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling

“…PAR-1 thrombin receptors are highly expressed in the heart and have many cardiovascular functions (21). Additionally, the 5-HT 2A receptor is highly expressed in vascular smooth muscle, pulmonary artery, and cardiac tissues.…”

Thrombin induced connective tissue growth factor expression in rat vascular smooth muscle cells via the PAR-1/JNK/AP-1 pathway

“…Overexpression of PAR-1 has been found in the VSMCs from thickening intimas of human atherosclerotic arteries [30] . Although subtypes of thrombin-responsive PARs, PAR-1, PAR-3, and PAR-4, are present and functionally active in VSMCs, PAR-1 has the highest affinity for thrombin [31] . PAR-1 is the prototypic thrombin receptor and the main isoform involved in VSMC neointimal formation and restenosis in vivo [32] , whereas PAR-3 appears to function as a cofactor for PAR-4 [33] .…”

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

“…[2][3][4] In endothelial cells, PAR1 contributes to endothelium-dependent relaxation or endothelium-dependent contraction, depending on the type of blood vessel (Figure). [5][6][7][8][9][10][11][12] PAR1 in endothelial cells also contributes to angiogenesis, 6,9 in addition to causing an alteration to the expression of multiple genes including cytokines, chemokines, and cell adhesion molecules (Figure). 13,14 In the smooth muscle cells, PAR1 mediates the contraction, cell migration, proliferation, hypertrophy, and production of the extracellular matrix ( Figure).…”

“…13,14 In the smooth muscle cells, PAR1 mediates the contraction, cell migration, proliferation, hypertrophy, and production of the extracellular matrix ( Figure). [5][6][7][8][9] Similarly, PAR2 also mediates endothelium-dependent relaxation and angiogenesis in endothelial cells, and mediates the contraction, cell migration, proliferation, hypertrophy and production of the extracellular matrix in the smooth muscle cells. [5][6][7][8][9] PAR3 functions as a cofactor for PAR4 activation, and therefore is not considered to directly elicit intracellular signals.…”

“…[5][6][7][8][9] Similarly, PAR2 also mediates endothelium-dependent relaxation and angiogenesis in endothelial cells, and mediates the contraction, cell migration, proliferation, hypertrophy and production of the extracellular matrix in the smooth muscle cells. [5][6][7][8][9] PAR3 functions as a cofactor for PAR4 activation, and therefore is not considered to directly elicit intracellular signals. 9,15 PAR4 has been reported to induce NO production in endothelial cells, 16 and an endothelium-dependent relaxation, [17][18][19] although its role in the smooth muscle cells remains unknown.…”