Protein kinase C isoforms as specific targets for modulation of vascular smooth muscle function in hypertension.
Vascular contraction is an important determinant of the peripheral vascular resistance and blood pressure. The mechanisms underlying vascular smooth muscle (VSM) contraction and the pathological changes that occur in hypertension have been the subject of numerous studies and interpretations. Activation of VSM by vasoconstrictor stimuli at the cell surface causes an increase in [Ca(2+)](i), Ca(2+)-dependent activation of myosin light chain (MLC) kinase, MLC phosphorylation, actin-myosin interaction and VSM contraction. Additional signaling pathways involving Rho-kinase and protein kinase C (PKC) may increase the myofilament force sensitivity to [Ca(2+)](i) and MLC phosphorylation, and thereby maintain vascular contraction. PKC is a particularly intriguing protein kinase as it comprises a family of Ca(2+)-dependent and Ca(2+)-independent isoforms, which have different tissue and subcellular distribution, and undergo differential translocation during cell activation. PKC translocation to the cell surface may trigger a cascade of protein kinases, such as mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) that ultimately interact with the contractile myofilaments and cause VSM contraction. Also, PKC translocation to the nucleus may promote VSM growth and proliferation. Increased PKC expression and activity have been identified in several forms of hypertension. The subcellular location of PKC may determine the state of VSM activity, and may be useful in the diagnosis/prognosis of hypertension. Vascular PKC isoforms may represent specific targets for modulation of VSM hyperactivity, and isoform-specific PKC inhibitors may be useful in treatment of Ca(2+) antagonist-resistant forms of hypertension.
Salamanca
Daisy A
DA
Harvard Medical School, Brigham and Women's Hospital, Division of Vascular Surgery, NRB 435, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Khalil
Raouf A
RA
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*
D000959:Antihypertensive Agents; D007527:Isoenzymes; D011493:Protein Kinase C