Reciprocal regulation of eNOS, H2S and CO-synthesizing enzymes in human atheroma: Correlation with plaque stability and effects of simvastatin

Fragiska Sigala, Panagiotis Efentakis, Dimitra Karageorgiadi, Konstadinos Filis, Paraskevas Zampas, Efstathios K. Iliodromitis, George Zografos, Andreas Papapetropoulos, Ioanna Andreadou

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)70-81
Number of pages12
JournalRedox Biology
Volume12
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

Fingerprint

Simvastatin
Atherosclerotic Plaques
Carbon Monoxide
Cystathionine beta-Synthase
Heme Oxygenase-1
Enzymes
Phosphorylation
Oxidative stress
Biomarkers
Oxidative Stress
Cystathionine gamma-Lyase
Endarterectomy
Guanylate Cyclase
Malondialdehyde
Carotid Arteries
Pathologic Constriction
Up-Regulation
Arteries
Chemical activation

Keywords

  • Carotid plaques
  • Heme oxygenase-1
  • Hydrogen sulfide
  • Nitric oxide
  • Nitro-oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

Cite this

Reciprocal regulation of eNOS, H2S and CO-synthesizing enzymes in human atheroma : Correlation with plaque stability and effects of simvastatin. / Sigala, Fragiska; Efentakis, Panagiotis; Karageorgiadi, Dimitra; Filis, Konstadinos; Zampas, Paraskevas; Iliodromitis, Efstathios K.; Zografos, George; Papapetropoulos, Andreas; Andreadou, Ioanna.

In: Redox Biology, Vol. 12, 01.08.2017, p. 70-81.

Research output: Contribution to journalArticle

Sigala, Fragiska ; Efentakis, Panagiotis ; Karageorgiadi, Dimitra ; Filis, Konstadinos ; Zampas, Paraskevas ; Iliodromitis, Efstathios K. ; Zografos, George ; Papapetropoulos, Andreas ; Andreadou, Ioanna. / Reciprocal regulation of eNOS, H2S and CO-synthesizing enzymes in human atheroma : Correlation with plaque stability and effects of simvastatin. In: Redox Biology. 2017 ; Vol. 12. pp. 70-81.
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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.",
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AU - Karageorgiadi, Dimitra

AU - Filis, Konstadinos

AU - Zampas, Paraskevas

AU - Iliodromitis, Efstathios K.

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AU - Papapetropoulos, Andreas

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