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Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease
Vascular Surgery Research Laboratory, Division of Vascular Surgery, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston 02115, MA, USA
Received: 11 December 2012; in revised form: 12 March 2013 / Accepted: 13 March 2013 / Published: 21 March 2013
Abstract: Blood pressure (BP) is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM) and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN). In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca2+ concentration ([Ca2+]i), which forms a complex with calmodulin, activates myosin light chain (MLC) kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC). PKC is a family of Ca2+-dependent and Ca2+-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK), a pathway that ultimately increases the myofilament force sensitivity to [Ca2+]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinases (MMPs) in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in concert with antioxidants, MMP inhibitors and cytokine antagonists to reduce VSM hyperactivity in certain forms of HTN that do not respond to Ca2+ channel blockers.
Keywords: calcium; endothelium; vascular smooth muscle; hypertension
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MDPI and ACS Style
Khalil, R.A. Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease. Pharmaceuticals 2013, 6, 407-439.
Khalil RA. Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease. Pharmaceuticals. 2013; 6(3):407-439.
Khalil, Raouf A. 2013. "Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease." Pharmaceuticals 6, no. 3: 407-439.