Preferences help
enabled [disable] Abstract
Number of results
2004 | 51 | 2 | 397-404
Article title

Physiology and pathophysiology of vascular signaling controlled by guanosine 3',5'-cyclic monophosphate-dependent protein kinase.

Title variants
Languages of publication
Recent medical advances suggest that the cellular natriuretic peptide/cGMP and NO/cGMP effector systems represent important signal transduction pathways especially in the cardiovascular system. These pathways also appear to be very interesting targets for the possible prevention of cardiovascular diseases. Exciting candidates for prevention include cGMP-dependent signaling networks initiated by natriuretic peptides (NP) and nitric oxide (NO) which are currently explored for their diagnostic and therapeutic potential. cGMP signaling contributes to the function and interaction of several vascular cell types, and its dysfunction is involved in the progression of major cardiovascular diseases such as atherosclerosis, hypertension and diabetic complications. This review will take a focussed look at key elements of the cGMP signaling cascade in vascular tissue. Recent advances in our knowledge of cGMP-dependent protein kinases (cGK, also known as PKG), the potential for assessing the functional status of cGMP signaling and the possible cross talk with insulin signaling will be reviewed.
Physical description
  • Institut für Klinische Biochemie und Pathobiochemie, Universitätsklinikum Würzburg, D-97078 Würzburg, Germany
  • Institut für Klinische Biochemie und Pathobiochemie, Universitätsklinikum Würzburg, D-97078 Würzburg, Germany
  • Aktas B, Utz A, Hoenig-Liedl P, Walter U, Geiger J. (2003) Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo studies. Stroke.; 34: 764-9.
  • Ammendola A, Geiselhoringer A, Hofmann F, Schlossmann J. (2001) Molecular determinants of the interaction between the inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) and cGMP kinase Iβ. J Biol Chem.; 276: 24153-9.
  • Begum N, Duddy N, Sandu O, Reinzie J, Ragolia L. (2000) Regulation of myosin-bound protein phosphatase by insulin in vascular smooth muscle cells: evaluation of the role of Rho kinase and phosphatidylinositol-3-kinase-dependent signaling pathways. Mol Endocrinol.; 14: 1365-76.
  • Bhatt DL, Topol EJ. (2003) Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov.; 2: 15-28.
  • Cohen RA, Vanhoutte PM. (1995) Endothelium-dependent hyperpolarization. Beyond nitric oxide and cyclic GMP. Circulation.; 92: 3337-49.
  • Etter EF, Eto M, Wardle RL, Brautigan DL, Murphy RA. (2001) Activation of myosin light chain phosphatase in intact arterial smooth muscle during nitric oxide-induced relaxation. J Biol Chem.; 276: 34681-5.
  • Fleming I, Schulz C, Fichtlscherer B, Kemp BE, Fisslthaler B, Busse R. (2003) AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets. Thromb Haemost.; 90: 863-71.
  • Fukao M, Mason HS, Britton FC, Kenyon JL, Horowitz B, Keef KD. (1999) Cyclic GMP-dependent protein kinase activates cloned BKCa channels expressed in mammalian cells by direct phosphorylation at serine 1072. J Biol Chem.; 274: 10927-35.
  • Furchgott RF, Zawadzki JV. (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature.; 288: 373-6.
  • Gambaryan S, Geiger J, Schwarz UR, Butt E, Begonja A, Obergfell A, Walter U. (2004) Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase. Blood.; 103: 2593-600.
  • Gewaltig MT, Kojda G. (2002) Vasoprotection by nitric oxide: mechanisms and therapeutic potential. Cardiovasc Res.; 55: 250-60.
  • Gunnett CA, Heistad DD, Faraci FM. (2003) Gene-targeted mice reveal a critical role for inducible nitric oxide synthase in vascular dysfunction during diabetes. Stroke.; 34: 2970-4.
  • Haslam RJ, Davidson MM, Davies T, Lynham JA, McClenaghan MD. (1978) Regulation of blood platelet function by cyclic nucleotides. Adv Cyclic Nucleotide Res.; 9: 533-52.
  • Hedlund P, Aszodi A, Pfeifer A, Alm P, Hofmann F, Ahmad M, Fassler R, Andersson KE. (2000) Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci USA.; 97: 2349-54.
  • Hofmann F, Ammendola A, Schlossmann J. (2000) Rising behind NO: cGMP-dependent protein kinases. J Cell Sci.; 113: 1671-6.
  • Hsueh WA, Law RE. (1999) Insulin signaling in the arterial wall. Am J Cardiol.; 84: 21J-4J.
  • Hu H, Hjemdahl P, Li N. (2002) Effects of insulin on platelet and leukocyte activity in whole blood. Thromb Res.; 107: 209-15.
  • Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA.; 84: 9265-9.
  • Katsuki S, Arnold W, Mittal C, Murad F. (1977) Stimulation of guanylate cyclase by sodium nitroprusside nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res.; 3: 23-35.
  • Li Z, Ajdic J, Eigenthaler M, Du X. (2003a) A predominant role for cAMP-dependent protein kinase in the cGMP-induced phosphorylation of vasodilator-stimulated phosphoprotein and platelet inhibition in humans. Blood.; 101: 4423-9.
  • Li Z, Xi Z, Gu M, Feil R, Ye RD, Eigenthaler M, Hofmann F, Du X. (2003b) A Stimulatory role for cGMP-dependent protein kinase in platelet activation. Cell.; 112: 77-86.
  • Lincoln TM, Dey N, Sellak H. (2001) Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression. J Appl Physiol.; 91: 1421-30.
  • Lohmann SM, Vaandrager AB, Smolenski A, Walter U, De Jonge HR. (1997) Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem Sci.; 22: 307-12.
  • Marshall SJ, Senis YA, Auger JM, Feil R, Hofmann F, Salmon G, Peterson JT, Burslem F, Watson SP. (2004) GPIb-dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP-dependent kinase. Blood.; 103: 2601-9.
  • Massberg S, Sausbier M, Klatt P, Bauer M, Pfeifer A, Siess W, Fassler R, Ruth P, Krombach F, Hofmann F. (1999) Increased adhesion and aggregation of platelets lacking cyclic guanosine 3',5'-monophosphate kinase I. J Exp Med.; 189: 1255-64.
  • McKendrick JD, Salas E, Dube GP, Murat J, Russell JC, Radomski MW. (1998) Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin-resistant obese JCR:LA-cp rats. Br J Pharmacol.; 124: 361-9.
  • Munzel T, Feil R, Mulsch A, Lohmann SM, Hofmann F, Walter U. (2003) Physiology and pathophysiology of vascular signaling controlled by guanosine 3'5'-cyclic monophosphate-dependent protein kinase [corrected]. Circulation.; 108: 2172-83.
  • Nolte C, Eigenthaler M, Horstrup K, Honig-Liedl P, Walter U. (1994) Synergistic phosphorylation of the focal adhesion-associated vasodilator-stimulated phosphoprotein in intact human platelets in response to cGMP- and cAMP-elevating platelet inhibitors. Biochem Pharmacol.; 48: 1569-75.
  • Ny L, Pfeifer A, Aszodi A, Ahmad M, Alm P, Hedlund P, Fassler R, Andersson KE. (2000) Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP-dependent protein kinase I. Br J Pharmacol.; 129: 395-401.
  • Palmer RM, Ferrige AG, Moncada S. (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature.; 327: 524-6.
  • Pfeifer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fassler R. (1996) Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II. Science.; 274: 2082-6.
  • Pfeifer A, Klatt P, Massberg S, Ny L, Sausbier M, Hirneiss C, Wang GX, Korth M, Aszodi A, Andersson KE, Krombach F, Mayerhofer A, Ruth P, Fassler R, Hofmann F. (1998) Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J.; 17: 3045-51.
  • Pfitzer G. (2001) Invited review: regulation of myosin phosphorylation in smooth muscle. J Appl Physiol.; 91: 497-503.
  • Ruth P. (1999) Cyclic GMP-dependent protein kinases: understanding in vivo functions by gene targeting. Pharmacol Ther.; 82: 355-72.
  • Sandu OA, Ragolia L, Begum N. (2000) Diabetes in the Goto-Kakizaki rat is accompanied by impaired insulin-mediated myosin-bound phosphatase activation and vascular smooth muscle cell relaxation. Diabetes.; 49: 2178-89.
  • Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, Chardin P, Pacaud P, Loirand G. (2000) Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem.; 275: 21722-9.
  • Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P. (2000) Regulation of intracellular calcium by a signalling complex of IRAG IP3 receptor and cGMP kinase Ibeta. Nature.; 404: 197-201.
  • Schultz KD, Schultz K, Schultz G. (1977) Sodium nitroprusside and other smooth muscle-relaxants increase cyclic GMP levels in rat ductus deferens. Nature.; 265: 750-1.
  • Schwarz UR, Walter U, Eigenthaler M. (2001) Taming platelets with cyclic nucleotides. Biochem Pharmacol.; 62: 1153-61.
  • Somlyo AP, Somlyo AV. (1994) Signal transduction and regulation in smooth muscle. Nature.; 372: 231-6.
  • Sowers JR, Epstein M. (1995) Diabetes mellitus and associated hypertension vascular disease and nephropathy. An update. Hypertension.; 26: 869-79.
  • Sowers JR, Epstein M, Frohlich ED. (2001) Diabetes hypertension and cardiovascular disease: an update. Hypertension.; 37: 1053-9.
  • Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. (1996) Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest.; 97: 2601-10.
  • Tschoepe D, Roesen P, Schwippert B, Gries FA. (1993) Platelets in diabetes: the role in the hemostatic regulation in atherosclerosis. Semin Thromb Hemost.; 19: 122-8.
  • Vaandrager AB, Bot AG, Ruth P, Pfeifer A, Hofmann F, De Jonge HR. (2000) Differential role of cyclic GMP-dependent protein kinase II in ion transport in murine small intestine and colon. Gastroenterology.; 118: 108-14.
  • von der Leyen HE, Dzau VJ. (2001) Therapeutic potential of nitric oxide synthase gene manipulation. Circulation.; 103: 2760-5.
  • Wagner C, Pfeifer A, Ruth P, Hofmann F, Kurtz A. (1998) Role of cGMP-kinase II in the control of renin secretion and renin expression. J Clin Invest.; 102: 1576-82.
  • Young DV, Serebryanik D, Janero DR, Tam SW. (2000) Suppression of proliferation of human coronary artery smooth muscle cells by the nitric oxide donor S-nitrosoglutathione is cGMP-independent. Mol Cell Biol Res Commun.; 4: 32-36.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.