cGMP-Dependent Protein Kinase Contributes to Hydrogen Sulfide-Stimulated Vasorelaxation

Mariarosaria Bucci, Andreas Papapetropoulos, Valentina Vellecco, Zongmin Zhou, Altaany Zaid, Panagiotis Giannogonas, Anna Cantalupo, Sandeep Dhayade, Katia P. Karalis, Rui Wang, Robert Feil, Giuseppe Cirino

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Abstract

A growing body of evidence suggests that hydrogen sulfide (H 2 S) is a signaling molecule in mammalian cells. In the cardiovascular system, H 2 S enhances vasodilation and angiogenesis. H 2 S-induced vasodilation is hypothesized to occur through ATP-sensitive potassium channels (K ATP ); however, we recently demonstrated that it also increases cGMP levels in tissues. Herein, we studied the involvement of cGMP-dependent protein kinase-I in H 2 S-induced vasorelaxation. The effect of H 2 S on vessel tone was studied in phenylephrine-contracted aortic rings with or without endothelium. cGMP levels were determined in cultured cells or isolated vessel by enzyme immunoassay. Pretreatment of aortic rings with sildenafil attenuated NaHS-induced relaxation, confirming previous findings that H 2 S is a phosphodiesterase inhibitor. In addition, vascular tissue levels of cGMP in cystathionine gamma lyase knockouts were lower than those in wild-type control mice. Treatment of aortic rings with NaHS, a fast releasing H 2 S donor, enhanced phosphorylation of vasodilator-stimulated phosphoprotein in a time-dependent manner, suggesting that cGMP-dependent protein kinase (PKG) is activated after exposure to H 2 S. Incubation of aortic rings with a PKG-I inhibitor (DT-2) attenuated NaHS-stimulated relaxation. Interestingly, vasodilatory responses to a slowly releasing H 2 S donor (GYY 4137) were unaffected by DT-2, suggesting that this donor dilates mouse aorta through PKG-independent pathways. Dilatory responses to NaHS and L-cysteine (a substrate for H 2 S production) were reduced in vessels of PKG-I knockout mice (PKG-I-/-). Moreover, glibenclamide inhibited NaHS-induced vasorelaxation in vessels from wild-type animals, but not PKG-I-/-, suggesting that there is a cross-talk between K ATP and PKG. Our results confirm the role of cGMP in the vascular responses to NaHS and demonstrate that genetic deletion of PKG-I attenuates NaHS and L-cysteine-stimulated vasodilation.

Original languageEnglish (US)
Article numbere53319
JournalPloS one
Volume7
Issue number12
DOIs
StatePublished - Dec 28 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Bucci, M., Papapetropoulos, A., Vellecco, V., Zhou, Z., Zaid, A., Giannogonas, P., Cantalupo, A., Dhayade, S., Karalis, K. P., Wang, R., Feil, R., & Cirino, G. (2012). cGMP-Dependent Protein Kinase Contributes to Hydrogen Sulfide-Stimulated Vasorelaxation. PloS one, 7(12), [e53319]. https://doi.org/10.1371/journal.pone.0053319