Hypertension in Mice Lacking 3-Mercaptopyruvate Sulfurtransferase

Background

3-mercaptopyruvate sulfurtransferase (3MST) is an enzyme involved in the production of hydrogen sulfide (H2S) and reactive sulfur species (supersulfides), which possess a variety of biological effects. 3MST is ubiquitously expressed, including in the vascular endothelial and smooth muscle cells, but its role in the regulation of blood pressure is not fully understood. In this study, we investigated the role of 3MST in blood pressure regulation using mice lacking the 3MST gene. Methods and Results: Experiments were performed in 6- to 16- week-old male 3MST-deficient (KO) mice and their wild-type (WT) littermates. The absence of 3MST mRNA and protein expression in the 3MST-KO mice was confirmed by reversetranscription PCR and Western blotting, respectively. Systolic blood pressure, assessed by the tail-cuff method and the telemetry system, was significantly higher in the 3MST-KO mice than in the WT mice. Peripheral vascular resistance, estimated from blood flow in the ascending aorta and arterial blood pressure in the femoral artery, was also significantly higher in the 3MST-KO mice than in the WT mice. In isolated mesenteric arteries, contractions to KCl and phenylephrine were significantly augmented, and acetylcholine (ACh)-induced endotheliumdependent relaxations were significantly impaired in the 3MST-KO mice. In particular, the prostacyclin (prostaglandin I2: PGI2)-mediated component of ACh-induced relaxations was significantly reduced in the 3MST-KO mice, accompanied by reduced plasma concentrations of 6-keto PGF1α, a stable metabolite of PGI2, and increased cardiac mRNA expression of phosphodiesterase 2A. Consistent with these findings, gene ontology and pathway analyses of RNA-sequencing data suggested the possible involvement of vasoconstriction and impaired cAMP signaling. Furthermore, cardiac angiotensin II type 1 (AT1) receptor mRNA expression and urinary 8-isoprostane excretion, a marker of oxidative stress, were significantly increased, and cardiac atrial natriuretic peptide (ANP) mRNA expression and plasma ANP concentrations were significantly reduced in the 3MST-KO mice.