CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway

Antonia Katsouda; Maria Markou; Paraskevas Zampas; Aimilia Varela; Constantinos H Davos; Valentina Vellecco; Giuseppe Cirino; Mariarosaria Bucci; Andreas Papapetropoulos

doi:10.3389/fphar.2023.1090654

CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway

Front Pharmacol. 2023 Feb 13:14:1090654. doi: 10.3389/fphar.2023.1090654. eCollection 2023.

Authors

Affiliations

¹ Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
² Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
³ Department of Pharmacy, School of Medicine and Surgery, University of Naples, Federico II, Naples, Italy.

Abstract

Hydrogen sulfide (H₂S), a gasotransmitter with protective effects in the cardiovascular system, is endogenously generated by three main enzymatic pathways: cystathionine gamma lyase (CTH), cystathionine beta synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes. CTH and MPST are the predominant sources of H₂S in the heart and blood vessels, exhibiting distinct effects in the cardiovascular system. To better understand the impact of H₂S in cardiovascular homeostasis, we generated a double Cth/Mpst knockout (Cth/Mpst ^-/- ) mouse and characterized its cardiovascular phenotype. CTH/MPST-deficient mice were viable, fertile and exhibited no gross abnormalities. Lack of both CTH and MPST did not affect the levels of CBS and H₂S-degrading enzymes in the heart and the aorta. Cth/Mpst ^-/- mice also exhibited reduced systolic, diastolic and mean arterial blood pressure, and presented normal left ventricular structure and fraction. Aortic ring relaxation in response to exogenously applied H₂S was similar between the two genotypes. Interestingly, an enhanced endothelium-dependent relaxation to acetylcholine was observed in mice in which both enzymes were deleted. This paradoxical change was associated with upregulated levels of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) α1 and β1 subunits and increased NO-donor-induced vasorelaxation. Administration of a NOS-inhibitor, increased mean arterial blood pressure to a similar extent in wild-type and Cth/Mpst ^-/- mice. We conclude that chronic elimination of the two major H₂S sources in the cardiovascular system, leads to an adaptive upregulation of eNOS/sGC signaling, revealing novel ways through which H₂S affects the NO/cGMP pathway.

Keywords: aorta; blood pressure; cystathine γ-lyase; hydrogen sulfide; mercaptopyruvate sulfurtransferase; nitric oxide synthase; vasorelaxation.

Grants and funding

The research work was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project number: HFRI-FM17-886).