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Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2005 Apr 08; Vol. 280 (14), pp. 13503-11. Date of Electronic Publication: 2005 Feb 10. - Publication Year :
- 2005
-
Abstract
- Cardiac stem cells or myoblasts are vulnerable to inflammatory stimulation in hearts with infarction or ischemic injury. Widely used for the prevention and treatment of atherosclerotic heart disease, the cholesterol-lowering drugs statins may exert anti-inflammatory effects. In this study, we examined the impact of inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase with simvastatin on the expression of inducible nitric-oxide synthase (iNOS) in embryonic cardiac myoblasts stimulated with the proinflammatory cytokines, interleukin-1 or tumor necrosis factor. Treatment with simvastatin significantly reduced the levels of iNOS mRNA and protein in cytokine-treated rat H9c2 cardiac embryonic myoblasts. Addition of the HMG-CoA reductase product, L-mevalonate, and the by-product of cholesterol synthesis, geranylgeranyl pyrophosphate, could reverse the statin inhibitory effect on iNOS expression. Simvastatin treatment lowered the Rho GTPase activities, whereas the Rho-associated kinase inhibitor Y27632 partially blocked the statin inhibitory effect on nitrite production in the cytokine-treated H9c2 cells. Treatment with simvastatin led to inactivation of NF-kappaB by elevation of the NF-kappaB inhibitor IkappaB and reduction of the NF-kappaB nuclear contents in the cytokine-stimulated H9c2 cells. Hence, treatment with simvastatin can attenuate iNOS expression and NO synthesis in cytokine-stimulated embryonic cardiac myoblasts. The statin inhibitory effect may occur through isoprenoid-mediated intracellular signal transduction, which involves several key signal proteins, such as Rho kinase and IkappaB/NF-kappaB. These data suggest that statin therapy may protect the cardiac myocyte progenitors against the cytotoxicity of cytokine-induced high output of NO production in infarcted or ischemic hearts with inflammation.
- Subjects :
- Animals
Cell Line
Embryo, Mammalian anatomy & histology
Humans
I-kappa B Kinase
Interleukin-1 pharmacology
Mevalonic Acid metabolism
NF-kappa B metabolism
Nitric Oxide Synthase genetics
Nitric Oxide Synthase Type II
Nitrites metabolism
Polyisoprenyl Phosphates metabolism
Protein Serine-Threonine Kinases metabolism
RNA, Messenger metabolism
Rats
Tumor Necrosis Factor-alpha pharmacology
rho GTP-Binding Proteins antagonists & inhibitors
rho GTP-Binding Proteins metabolism
Embryo, Mammalian physiology
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Myoblasts, Cardiac drug effects
Myoblasts, Cardiac enzymology
Nitric Oxide Synthase metabolism
Simvastatin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15705589
- Full Text :
- https://doi.org/10.1074/jbc.M411859200