title: Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders.
abstract: Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca2+-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca2+-dependent α, β, and γ, novel Ca2+-independent δ, ɛ, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation, and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a process facilitated by scaffold proteins such as RACKs. Activated PKC phosphorylates different substrates including ion channels, pumps, and nuclear proteins. PKC also phosphorylates CPI-17 leading to inhibition of MLC phosphatase, increased MLC phosphorylation, and enhanced VSM contraction. PKC could also initiate a cascade of protein kinases leading to phosphorylation of the actin-binding proteins calponin and caldesmon, increased actin-myosin interaction, and VSM contraction. Increased PKC activity has been associated with vascular disorders including ischemia-reperfusion injury, coronary artery disease, hypertension, and diabetic vasculopathy. PKC inhibitors could test the role of PKC in different systems and could reduce PKC hyperactivity in vascular disorders. First-generation PKC inhibitors such as staurosporine and chelerythrine are not very specific. Isoform-specific PKC inhibitors such as ruboxistaurin have been tested in clinical trials. Target delivery of PKC pseudosubstrate inhibitory peptides and PKC siRNA may be useful in localized vascular disease. Further studies of PKC and its role in VSM should help design isoform-specific PKC modulators that are experimentally potent and clinically safe to target PKC in vascular disease.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: H C
authors.initials: HC
authors.lastname: Ringvold
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. Electronic address: raouf_khalil@hms.harvard.edu.
authors.forename: R A
authors.initials: RA
authors.lastname: Khalil
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D014652:Vascular Diseases / Q000503:physiopathology*; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D007211:Indoles; D008301:Maleimides; D018994:Myosin Light Chains; C099154:ruboxistaurin; D011493:Protein Kinase C; D002118:Calcium
keywords: Blood vessels; Calcium; Contraction; Hypertension; Protein kinases; Signaling