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.
Highlights
Hypertension (HTN) is a major cardiovascular and renal disease affecting a large proportion of the population in the Western World
The blood vessel wall has three layers; the tunica intima made of a single layer of endothelial cells (ECs), the tunica media made of several layers of vascular smooth muscle cells (VSMCs), and the adventitia made of fibroblasts, connective tissue and extracellular matrix (ECM)
protein kinase C (PKC) L, is the human homologue of mouse -PKC [34]. -PKC consists of 707 amino acids and shows the highest sequence similarity to -PKC (67% identity) [33]. aPKCs include and / PKC, and characteristically have only one Cys-rich zinc finger-like motif. aPKCs are dependent on phosphatidylserine, but are not affected by DAG, phorbol esters or Ca 2+, and do not translocate or downregulate in response to phorbol esters or DAG [30] (Table 1)
Summary
Hypertension (HTN) is a major cardiovascular and renal disease affecting a large proportion of the population in the Western World. The ability of VSMCs to contract and relax plays an important role in the regulation of the vessel diameter and blood flow to various tissues and organs. This review will focus on how vasoconstrictor agonists affect the mechanisms of VSM contraction protein kinase C (PKC), and the changes in these mechanisms in vascular disease such as HTN. In addition to changes in vasoactive factors, changes in reactive oxygen species (ROS) [1,2,3], MMPs and inflammatory cytokines [4,5,6] in the plasma and vascular tissues [7,8,9] have been observed in HTN and coronary artery disease. Understanding the role of PKC as a major regulator of VSM function, the PKC isoforms, their protein substrates and subcellular distribution, and their interaction with other factors such as ROS, MMPs and cytokines would provide important information regarding the benefits of determining.
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