Modulation of H 2 S Metabolism by Statins: A New Aspect of Cardiovascular Pharmacology

Abstract

Significance: Statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors) are commonly used in the treatment of cardiovascular diseases. Statins reduce plasma low-density lipoproteins, inhibit inflammatory reaction, improve endothelial function, ameliorate oxidative stress, and reduce platelet activity. Consequently, statins markedly decrease the risk of acute cardiovascular events. H₂S is synthesized in all layers of the vascular wall, including the endothelium, smooth muscle cells, and perivascular adipose tissue (PVAT). Recent Advances: Recent studies demonstrate that PVAT-derived H₂S decreases vascular tone by activating K_ATP and/or KCNQ potassium channels in smooth muscle cells. Lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H₂S production in PVAT by inhibiting its mitochondrial oxidation, and augments the anticontractile effect of PVAT. Inhibition of H₂S metabolism results from atorvastatin-induced decrease in coenzyme Q, which is a cofactor of H₂S oxidation by sulfide:quinone oxidoreductase. In contrast to H₂S, statins do not impair mitochondrial oxidation of organic substrates. Critical Issues: Taking into account antiatherosclerotic and anti-inflammatory effect of H₂S, the gas may mediate some of the beneficial effects of statins on the cardiovascular system. In addition, specific statins differ in their ability to enhance H₂S signaling. Future Directions: Since both statins and H₂S reduce ischemia-reperfusion injury, the possible effect of statins on H₂S oxidation in other tissues such as the heart and the kidney needs to be examined. Inhibition of H₂S metabolism may be a new therapeutic strategy to improve H₂S signaling, especially in the mitochondrial compartment. Antioxid. Redox Signal. 17, 81–94.