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.

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

“…The contributions below also highlight how RONS contribute to established signaling pathways by their redox modulation. The interactions of RONS with microparticles [37] , [38] , [39] , protein aggregates [40] , [41] and the gasotransmitter H 2 S [33] , [42] represent important examples that illustrate how RONS as messengers indirectly influence other signaling systems. Therefore, far from being merely biological waste products, RONS represent highly active and tightly regulated signaling molecules.…”

Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function

“…6A) and was reversed to normal levels in response to melatonin administration via activation of the AMPK/PGCα1 pathway. Mechanistically, mitochondria produce ATP via the respiratory electron-transport chain (ETC) (38,51). The activity of ETC was decreased by high glucose treatment ( Fig.…”

“…In the present study, mPTP opening was measured via tetramethylrhodamine ethyl ester (TMRE) fluorescence. Samples were washed three times with PBS and were then stained with TMRE dye (38). The baseline fluorescence of TMRE was recorded and, after 30 min, TMRE fluorescence was recorded again.…”

Plasma Cystathionine and Risk of Incident Stroke in Patients With Suspected Stable Angina Pectoris

“…Both these processes play a critical role in the pathogenesis of atherosclerotic disease9 and hence to clinical manifestations such as ischemic stroke 1, 10. Moreover, increased expression of cystathionine metabolizing enzymes have recently been found in human atherosclerotic lesions and are shown to exacerbate angiogenesis, thereby increasing the risk of plaque instability,11 often associated with atherothrombotic events 12. However, the role of plasma cystathionine in relation to stroke risk has not previously been reported.…”