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Study on the effects of the mitochondria-targeted hydrogen sulfide (H2S)-donor AP39 on vascular endothelial and smooth muscle cells in culture.

Abstract

The vasorelaxant effects of the endogenous gasotransmitter hydrogen sulfide (H2S), as well as those of its donor compounds, have been demonstrated in some vascular beds. These findings, added to the antioxidant, anti-inflammatory and stimulatory effects of mitochondrial function, make of H2S and its donors, compounds with interesting therapeutic potential for treatment of vascular diseases. Particularly, in the case of the selective mitochondria-targeted H2S-donors (such as the compound AP39), the antioxidant activity in cultured endothelial cells subjected to oxidative stress has been described, as well as its beneficial in vivo effects on myocardial ischemia and reperfusion (evaluated as reduction of associated tissue damage) and vasodilatation. In our laboratory, we have demonstrated the vasorelaxant activity of this compound in mouse mesenteric artery rings in vitro, which involves the participation of the endothelium (via activation of the NO-soluble guanylate cyclase pathway) and hyperpolarization (via potassium channels). However, it is not clear whether these effects are exclusively due to the donation of H2S at the mitochondrial level, as well as the apparent direct effects on smooth muscle (in addition to the endothelium, as already mentioned). In this way, the general objective of this project is to investigate the signaling mechanisms involved in the vasorelaxant effects of AP39 using cultures of vascular endothelial and smooth muscle cells. For this purpose, the effects of this compound will be studied on the endothelial production of NO (i.e., interference with mechanisms of eNOS phosphorylation via AKt, mobilization of Ca2+ and synthesis of the cofactor tetrahydrobiopterine - BH4), in addition to the endogenous antioxidant enzyme activity and mitochondrial function (as assessed by measurement of oxygen consumption and ATP production). (AU)

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