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Role of Reactive Oxygen Species and Sulfide-Quinone Oxoreductase in Hydrogen Sulfide-Induced Contraction of Rat Pulmonary Arteries

Role of Reactive Oxygen Species and Sulfide-Quinone Oxoreductase in Hydrogen Sulfide-Induced Contraction of Rat Pulmonary Arteries

Jesus Prieto-Lloret, Vladimir A Snetkov, Yasin Shaifta, Inmaculada Docio, Michelle J Connolly, Charles E MacKay, Greg A Knock, Jeremy P T Ward, Philip I Aaronson

Am J Physiol Lung Cell Mol Physiol. 2018 Apr 1;314(4):L670-L685.

PMID: 29351439

Abstract:

Application of H2S ("sulfide") elicits a complex contraction in rat pulmonary arteries (PAs) comprising a small transient contraction (phase 1; Ph1) followed by relaxation and then a second, larger, and more sustained contraction (phase 2; Ph2). We investigated the mechanisms causing this response using isometric myography in rat second-order PAs, with Na2S as a sulfide donor. Both phases of contraction to 1,000 μM Na2S were attenuated by the pan-PKC inhibitor Gö6983 (3 μM) and by 50 μM ryanodine; the Ca2+ channel blocker nifedipine (1 μM) was without effect. Ph2 was attenuated by the mitochondrial complex III blocker myxothiazol (1 μM), the NADPH oxidase (NOX) blocker VAS2870 (10 μM), and the antioxidant TEMPOL (3 mM) but was unaffected by the complex I blocker rotenone (1 μM). The bath sulfide concentration, measured using an amperometric sensor, decreased rapidly following Na2S application, and the peak of Ph2 occurred when this had fallen to ~50 μM. Sulfide caused a transient increase in NAD(P)H autofluorescence, the offset of which coincided with development of the Ph2 contraction. Sulfide also caused a brief mitochondrial hyperpolarization (assessed using tetramethylrhodamine ethyl ester), followed immediately by depolarization and then a second more prolonged hyperpolarization, the onset of which was temporally correlated with the Ph2 contraction. Sulfide application to cultured PA smooth muscle cells increased reactive oxygen species (ROS) production (recorded using L012); this was absent when the mitochondrial flavoprotein sulfide-quinone oxoreductase (SQR) was knocked down using small interfering RNA. We propose that the Ph2 contraction is largely caused by SQR-mediated sulfide metabolism, which, by donating electrons to ubiquinone, increases electron production by complex III and thereby ROS production.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP76706553	Myxothiazol		76706-55-3	Price

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