Role of PDE5/cGMP/cGMP-dependent Protein Kinase in Cardiac Hypertrophy and Remodeling

• Applicant: Professor Dr. Robert Lukowski
• Subject Area: Pharmacology
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 41489051

• Final Report Year: 2011

Final Report Abstract

During the first funding period of the FOR923 "Molecular Dissection of Cardiovascular Functions" we studied the role of cyclic guanosine-3',5'-monophosphate (cGMP)-dependent signaling molecules, such as the cGMP-dependent protein kinase I (cGKI) and phophodiesterases (PDEs) on cardiac remodeling and hypertrophy. Recent evidence suggested that the PDE-5 inhibitor sildenafil (SIL) controls the growth of the heart muscle probably through cardiomyocyte cGMP levels and cGKI activity. To provide the first genetic evidence of this hypothesis we established a novel mouse model that lacked cGKI in cardiac myoctes (CMs). In order to test whether the inactivation of the CM cGMP/cGKI pathway had consequences for the growth response of the heart we induced hypertrophy via constriction of the aorta (TAC) and by a chronic activation of the cardiac ß-adrenoreceptor. In both models we detected significant changes of heart mass, CM size, fibrosis and fetal gene markers as compared to sham or saline treated animals, but there were no differences between the gene-targeted cGKI mice and littermatched controls. Our data further suggest that the effects of SIL on hypertrophy might rather be mediated via the Ca2+/calmodulin activated PDE-1C than PDE-5. PDE-1C can hydrolyze both cAMP and cGMP equally well and we verified that it sensitive to SIL inhibition in the high nM range. Importantly, PDE-1C is present in CMs at baseline and after stress in the models used, whereas so far we could not detect PDE-5 in the same cells with various molecular and biochemical approaches.

Publications

• (2006). cGMP signals mainly through cAMP kinase in permeabilized murine aorta. Am J Physiol Heart Circ Physiol. 292, H237-244
  Wörner R., Lukowski R., Hofmann F., Wegener J.W.
  
• (2007). Rescue of cGMP kinase I knockout mice by smooth muscle specific expression of either isozyme. Circ Res. 101(11):1096-103
  Weber S., Bernhard D., Lukowski R., Weinmeister P., Wörner R., Wegener JW., Valtcheva N., Feil S., Schlossmann J., Hofmann F., Feil R.
  
• (2008) Anemia and splenomegaly in cGKldeficient mice. Proc Natl Acad Sci USA. 105:6771-6776
  Föller M, Feil S, Ghoreschi K, Koka S, Gerling A, Thunemann M, Hofmann F, Schuler B, Vogel J, Pichler B, Kasinathan RS, Nicolay JP, Huber SM, Lang F, Feil R
  
• (2008). cGMP-dependent protein kinase I promotes adhesion of primary vascular smooth muscle cells. Mol Biol Cell. 19(10):4434-41
  Weinmeister P., Lukowski R., Linder S., Traidl-Hoffmann C., Hengst L., Hofmann F., Feil R.
  
• (2008). Role of smooth muscle cGMP/cGKl signaling in murine vascular restenosis. Arterioscler Thromb Vasc Biol. 28(7):1244-50
  Lukowski R., Weinmeister P., Bernhard D., Fei S., Gotthardt M., Herz J., Massberg S., Zernecke A., Weber C. , Hofmann F., Feil R.
  
• (2009) cGMP kinase and RhoA Ser188 phosphorylation integrate pro-and anti-fibrotic signals in blood vessels. Mol Cell Biol 29:6018-6032
  Sawada N, Itoh H, Miyashita K, Tsujimoto H, Sone M, Yamahara K, Arany ZP, Hofmann F, Nakao K
  
• (2009) cGMP-dependent protein kinase I is crucial for angiogenesis and postnatal neovascularization. PLOS One 4: e4879
  Aicher A, Heeschen C, Feil S, Hofmann F, Mendelsohn ME, Feil R, Dimmeler, S
  
• (2009). cGMP regulated Protein Kinases. Handb Exp Pharmacol. (191 ):137-62
  Hofmann F., Bernhard D., Lukowski R., Weinmeister P.
  
• (2010) Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase type I in cardiomyocytes. Proc Natl Acad Sci USA . 107: 5646-5651
  Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F
  
• (2010) IRAG determines NO- and ANP-mediated smooth muscle relaxation. Cardiovasc Res 86, 496-505
  Desch M, Sigl K, Hieke B, Salb K, Kees F, Bernhard D, Jochim A, Spiessberger B, Höcherl K, Feil R, Feil S, Lukowski R, Wegener JW, Hofmann F, Schlossmann J
  
• (2010) Reply to Kass and Takimoto: Cardiac hypertrophy without cGKl and PDE5 in cardiac myocytes. Proe Natl Acad Sci USA . 107: E99
  Lukowski R, Rybalkin SD, Beavo JA, Hofmann F
  
• (2011) Cyclic GMP kinase I modulates glucagon release from pancreatic α-cells. Diabetes. 60:148- 156
  Leiss V, Friebe A, Welling A, Hofmann F, Lukowski R
  
• (2011). Kinetics of relaxation by cGMP/cGKl signalling in gastric smooth muscle. Eur J Pharmacol, Aug 19. [Epub ahead of print]
  ErtI C , Lukowski R., Sigl K., Schlossmann J., Hofmann F., Wegener J.W.