title: Reciprocal regulation of eNOS, H2S and CO-synthesizing enzymes in human atheroma: Correlation with plaque stability and effects of simvastatin.
abstract: The molecular and cellular mechanisms underlying plaque destabilization remain obscure. We sought to elucidate the correlation between NO, H2S and CO-generating enzymes, nitro-oxidative stress and plaque stability in carotid arteries. Carotid atherosclerotic plaques were collected from 62 patients who had undergone endarterectomy due to internal artery stenosis. Following histological evaluation the plaques were divided into stable and unstable ones. To investigate the impact of simvastatin we divided patients with stable plaques, into those receiving and to those not receiving simvastatin. Expression and/or levels of p-eNOS/eNOS, pAkt/t-Akt, iNOS, cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE), heme oxygenase-1(HO-1), soluble guanyl cyclase sGCα1, sGCβ1, NOX-4 and HIF-1α were evaluated. Oxidative stress biomarkers malondialdehyde (MDA) and nitrotyrosine (NT) were measured. NT levels were decreased in stable plaques with a concomitant increase of eNOS phosphorylation and expression and Akt activation compared to unstable lesions. An increase in HIF-1α, NOX-4, HO-1, iNOS, CBS and CSE expression was observed only in unstable plaques. 78% of patients under simvastatin were diagnosed with stable plaques whereas 23% of those not receiving simvastatin exhibited unstable plaques. Simvastatin decreased iNOS, HO-1, HIF-1α and CSE whilst it increased eNOS phosphorylation. In conclusion, enhanced eNOS and reduced iNOS and NOX-4 were observed in stable plaques; CBS and CSE positively correlated with plaque vulnerability. Simvastatin, besides its known effect on eNOS upregulation, reduced the HIF-1α and its downstream targets. The observed changes might be useful in developing biomarkers of plaque stability or could be targets for pharmacothepary against plaque vulnerability.
authors.affiliation: National and Kapodistrian University of Athens Medical School, First Department of Surgery, Athens, Greece.
authors.forename: Fragiska
authors.initials: F
authors.lastname: Sigala
authors.affiliation: National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Efentakis
authors.affiliation: National and Kapodistrian University of Athens Medical School, First Department of Surgery, Athens, Greece; National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Athens, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Karageorgiadi
authors.affiliation: National and Kapodistrian University of Athens Medical School, First Department of Surgery, Athens, Greece.
authors.forename: Konstadinos
authors.initials: K
authors.lastname: Filis
authors.affiliation: National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Athens, Greece.
authors.forename: Paraskevas
authors.initials: P
authors.lastname: Zampas
authors.affiliation: National and Kapodistrian University of Athens, Medical School, Second University Dept. of Cardiology, Athens, Greece.
authors.forename: Efstathios K
authors.initials: EK
authors.lastname: Iliodromitis
authors.affiliation: National and Kapodistrian University of Athens Medical School, First Department of Surgery, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Zografos
authors.affiliation: National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.affiliation: National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Athens, Greece. Electronic address: jandread@pharm.uoa.gr.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016893:Carotid Stenosis / Q000188:drug therapy / Q000601:surgery*; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000074663:NADPH Oxidase 4 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019821:Simvastatin; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; C498910:NOX4 protein, human; D051057:Proto-Oncogene Proteins c-akt; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: Carotid plaques; Heme oxygenase-1; Hydrogen sulfide; Nitric oxide; Nitro-oxidative stress