title: Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts.
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.
authors.affiliation: Institute of Cardiology and Center of Excellence on Aging, G. d'Annuzio Univeristy, Chieti, Italy.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Madonna
authors.forename: Pericle
authors.initials: P
authors.lastname: Di Napoli
authors.forename: Marika
authors.initials: M
authors.lastname: Massaro
authors.forename: Alfredo
authors.initials: A
authors.lastname: Grilli
authors.forename: Mario
authors.initials: M
authors.lastname: Felaco
authors.forename: Alberto
authors.initials: A
authors.lastname: De Caterina
authors.forename: Daming
authors.initials: D
authors.lastname: Tang
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
mesh_terms: D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D009573:Nitrites; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020741:rho GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid