cGMP-dependent protein kinases and their significance for cardiovascular function
Project management at the University of Würzburg:
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.
Projekt period: from 01.1999 to 12.2001
DFG ,Granting date: 12.02.1998