Patrucco, Enrico and Domes, Katrin and Sbroggio, Mauro and Blaich, Anne and Schlossmann, Jens and Desch, Matthias and Rybalkin, Sergei D. and Beavo, Joseph A. and Lukowski, Robert and Hofmann, Franz (2014) Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111 (35). pp. 12925-12929. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)Abstract
Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKI beta only in smooth muscle (beta RM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, beta RM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged beta RM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg.kg(-1).d(-1)) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in beta RM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGF beta, and CTGF mRNA in Ctr but not in beta RM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PRESERVED EJECTION FRACTION; ATRIAL-NATRIURETIC-PEPTIDE; GROWTH-FACTOR-BETA; CYCLIC-GMP; MYOCARDIAL-INFARCTION; RECEPTOR; MICE; CARDIOMYOCYTES; INHIBITION; CHANNELS; PKGI; PDE; cardiac failure; hypertension; NO/cyclic GMP system |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Aug 2019 09:43 |
| Last Modified: | 14 Aug 2019 09:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9572 |
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