Differential effects of statins on endogenous H2S formation in perivascular adipose tissue

Hydrogen sulfide (H2S) is a new gasotransmitter synthesized enzymatically from L-cysteine in cytosol and is oxidized in mitochondria. In the cardiovascular system, H2S regulates vascular tone, inhibits atherogenesis, and protects against myocardial ischemia-reperfusion injury. We examined the effect of statins on vascular H2S production. Male Wistar rats received pravastatin (40 mg/kg/day) or atorvastatin (20 mg/kg/day) for 3 weeks and then H2S formation was measured in aortic media, periaortic adipose tissue (PAAT) and the liver. Only atorvastatin increased H2S production in PAAT whereas both statins stimulated its formation in the liver. Neither statin affected H2S production in aortic media. H2S formation in post-mitochondrial supernatant was higher than in mitochondria-containing supernatant and was not influenced by statins in any tissue. In addition, oxidation of exogenous H2S in isolated liver mitochondria was slower in statin-treated than in control rats. These data indicate that statins increase net H2S production by inhibiting its mitochondrial oxidation. Statins had no effect on the activity of H2S-metabolizing enzyme, sulfide:quinone oxidoreductase, measured at saturating coenzyme Q concentration. Both statins reduced CoQ(9) concentration in plasma and liver, but only atorvastatin decreased- CoQ(9) in PAAT. Atorvastatin attenuated phenylephrine-induced contraction of PAAT+ but not of PAAT aortic rings. Effects of atorvastatin on net H2S production, mitochondrial H2S oxidation and aortic contractility were abolished by supplementation of exogenous CoQ(9). In conclusion, lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H2S production in perivascular adipose tissue by inhibiting its mitochondrial oxidation. This effect is mediated by statin-induced CoQ(9) deficiency and results in the augmentation of anticontractile effect of perivascular adipose tissue. (C) 2010 Elsevier Ltd. All rights reserved.