cGMP-dependent protein kinases and their significance for cardiovascular function
Project management at the University of Würzburg:
- Dr. med. habil. Suzanne Lohmann (PhD, MD)
, Institut für Klinische Biochemie und Pathobiochemie, Josef-Schneider-Str. 2, 97080 Würzburg,Tel: 0931-201-45457,Fax: 0931-201-45137,Mail: email@example.com
Teilprojekt B4 examines the involvement of cGMP-dependent protein kinase (cGK) in the signaling pathway by which natriuretic peptides (ANP, BNP) and nitric oxide exert their extensive effects on the cardiovascular system, including effects which oppose hypertension, volume overload, and cardiac hypertrophy and failure. Our results show that in cultured neonatal cardiac myocytes cGK Ia displays anti-hypertrophic effects which are now being tested in a heart-specific transgenic cGK Ia mouse. These studies will also be refined and extended using tetracycline-regulated transgenic expression of heart-specific constitutive cGK Ia, as well as crosses with transgenic mice displaying cardiac hypertrophy. Mice will be analyzed with respect to their cardiac function, as well as effects of cGK Ia on cardiac signaling pathways involving Ca2+, phospholamban, troponin I, and the ryanodine receptor. Although natriuretic peptides have salutory effects on cardiac function, in congestive heart failure (CHF), an attenuated response to natriuretic peptides is observed which may be partly due to desensitization of the receptor by dephosphorylation. cGK involvement in the ANP/BNP receptor (GC-A) phosphorylation state and desensitization will be analyzed. Also, in addition to endogenous cGK Ia in cardiac myocytes, our data demonstrate endogenous cGK II associated with sites of ANP storage, therefore, the role of cGK I and II in regulation of ANP secretion will be investigated. Another hallmark of CHF, as well as of BNP null mice, is cardiac fibrosis which eventually severely compromises cardiac function. Mouse cardiac fibroblasts contain endogenous cGK I, and data from others suggests that cGMP opposes fibroblast proliferation and extracellular matrix production, therefore we are analyzing the effect of cGK I activation on gene expression in these cells using the comprehensive screening method SAGE (serial analysis of gene expression). A long-range goal will be to understand inhibition of the proliferative and fibrotic process in order to distinguish beneficial wound repair from excessive and debilitating fibrosis.
cGMP-dependent protein kinase
nitric oxide synthase
cardiac hypertrophy and failure
from 01.1999 to 12.2001
DFG ,Granting date: 02.12.1998
- Hoenderop JGJ, Vaandrager AB, Dijkink L, Smolenski A, Gambaryan S, Lohmann SM, de Jonge HR, Willems PHGM, Bindels RJM.
(1999). Atrial natriuretic peptide-stimulated Ca2+ reabsorption in rabbit kidney requires membrane-targeted cGMP-dependent protein kinase type II. (monograph)
- Gudi T, Hong GK-P, Vaandrager AB, Lohmann SM, Pilz RB.
(1999). Nitric oxide and cGMP regulate gene expression in neuronal and glial cells by activating type II cGMP-dependent protein kinase. (monograph)
- Butt E, Bernhardt M, Smolenski A, Kotsonis P, Fröhlich LG, Sickmann A, Meyer HE, Lohmann SM, Schmidt HHHW.
(2000). Endothelial nitric oxide synthase (type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases. (monograph)
- Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio, J, Chardin P, Pacaud P, Loirand G.
(2000). cGMP-dependent protein kinase signaling pathway inhibits Rho A-induced Ca2+ sensitization of contraction in vascular smooth muscle. (monograph)
- Smolenski A, Poller W, Walter U, Lohmann SM.
(2000). Regulation of human endothelial cell focal adhesion sites and migration by cGMP-dependent protein kinase I. (monograph)
- Arancio O, Antonova I, Gambaryan S, Lohmann SM, Wood JS, Lawrence DS, Hawkins RD.
(2001). Presynaptic role of cGMP-dependent protein kinase during long-lasting potentiation. (monograph)
- Fischer TA, Palmetshofer A, Gambaryan S, Butt E, Jassoy C, Walter U, Sopper S Lohmann SM.
(2001). Activation of cGMP-dependent protein kinase Iß inhibits interleukin 2 release and proliferation of T cell receptor-stimulated human peripheral T cells. (monograph)
- Hanada S, Terada Y, Inoshita S, Sasaki S, Lohmann SM, Smolenski A, and Marumo F.
(2001). Overexpression of protein kinase G using adenovirus inhibits cyclin E transcription and mesangial cell cycle. (monograph)
- de Vente J, Asan E, Gambaryan S, Markerink-van Ittersum M, Axer H, Gallatz K, Lohmann SM, Palkovits M.
(2001). Localization of cGMP-dependent protein kinase type II in rat brain. (monograph)
- Wollert KC, Fiedler B, Gambaryan S, Smolenski A, Heineke J, Butt E, Trautwein C, Lohmann SM, Drexler H.
(2002). Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects of nitric oxide in cardiomyocytes. (monograph)
- Begum N, Sandu OA, Ito M, Lohmann SM, Smolenski A.
(2002). Active Rho kinase (ROK-a) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. (monograph)
- Pierkes M, Gambaryan S, Boknik P, Lohmann SM, Schmitz W, Potthast R, Holtwick R, Kuhn M.
(2002). Increased effects of C-type natriuretic peptide on cardiac ventricular contractility and relaxation in guanylyl cyclase A-deficient mice. (monograph)
- Gambaryan, S, Palmetshofer A, Glazova M, Smolenski, A, Kristjansson GI, Zimmer M, Lohmann SM.
(2002). Inhibition of cGMP-dependent protein kinase II by its own splice isoform. (monograph)
- Jacob A, Molkentin JD, Smolenski A, Lohmann SM, Begum N.
(2002). Insulin inhibits PDGF-directed VSMC migration via NO/cGMP increase of MKP-1 and its inactivation of MAPKs. (monograph)
- Fiedler B, Lohmann SM, Smolenski A, Linnemüller S, Pieske B, Schröder F, Molkentin JD, Drexler H, Wollert KC.
(2002). Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase I in cardiac myocytes.. (monograph)
Institute for Clinical Biochemistry and Pathobiochemistry
Central Laboratory, University Hospital Würzburg