Aims. We object to elucidate that protective effect of H₂S on endothelium is mediated by downregulating BMP4 (bone morphogenetic protein 4)/cyclooxygenase‐ (COX‐) 2 pathway in rats with hypertension. Methods and Results. The hypertensive rat model induced by two‐kidney one‐clip (2K1C) model was used. Exogenous NaHS administration (56 μmol/kg/day, intraperitoneally once a day) reduced mean arterial pressure (MAP) of 2K1C rats from 199.9 ± 3.312 mmHg to 159.4 ± 5.434 mmHg, while NaHS did not affect the blood pressure in the Sham rats and ameliorated endothelium‐dependent contractions (EDCs) of renal artery in 2K1C rats. 2K1C reduced CSE level twofold, decreased plasma levels of H₂S about 6‐fold, increased BMP4, Nox2, and Nox4 levels 2‐fold and increased markers of oxidative stress MDA and nitrotyrosine 1.5‐fold, upregulated the expression of phosphorylation‐p38 MAPK 2‐fold, and increased protein levels of COX‐2 1.5‐fold, which were abolished by NaHS treatment. Conclusions. Our results demonstrate that H₂S prevents activation of BMP4/COX‐2 pathway in hypertension, which may be involved in the ameliorative effect of H₂S on endothelial impairment. These results throw light on endothelial protective effect of H₂S and provide new target for prevention and therapy of hypertension.

Hydrogen sulfide (H₂S) is an important endogenous gaseous transmitter in many physiological functions. Plasma H₂S decreased, and angiotensin II (Ang II) type 1 receptor (AT1R) increased in the myocardial tissues in 2-kidney 1-clip (2K1C) rats than in normotensive rats. Accumulating evidences suggest that H₂S inhibited Ang II/AT1R pathway to regulate cardiovascular function. Therefore, we hypothesized that H₂S may exert beneficial effects on myocardial remodeling in 2K1C rat models of renovascular hypertension. Sodium hydrosulfide (NaHS, 56 µmol/kg/day) was administered intraperitoneally to the rats from the 7th day after 2K1C operation. Systolic blood pressure was significantly increased from the first week after the operation and was lowered after NaHS treatment for 4 weeks. H₂S could also inhibit the ratio of left ventricle and septum weight to body weight, improve cross-sectional area, and ameliorate ventricular dysfunction. Additionally, the protein expression of AT1R and Ang II serum content were downregulated, whereas superoxide dismutase (SOD) protein was upregulated in 2K1C rats by NaHS treatment for 4 weeks. Furthermore, the reactive oxygen species level and AT1R protein were increased, whereas SOD protein was decreased in cardiomyocytes treated with Ang II compared with the control group. NaHS could reverse these changes. Losartan and N-acetylcysteine could also reverse Ang II-induced changes. The protective effect of H₂S is attributable to the suppression of oxidative stress. This process involves the inhibition of the Ang II/AT1R pathway and upregulation of antioxidant enzymes in 2K1C rats.

A large number of studies have shown hypertension of offspring in adulthood is related to parental health during pregnancy. Hydrogen sulfide (H₂S) could relax placental vasculature and improve intrauterine growth restriction. In the present study, we want to observe the effect of H₂S on the fetal programming of renovascular hypertension, a rat model of secondary hypertension. Renovascular hypertension was induced by 2-kidney-1-clip, their adult pups were used to evaluate basal blood pressure. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured noninvasively by tail-cuff plethysmography in conscious offspring; HE staining was used to observe morphology of kidney; the protein expression of angiotensin II receptor 1 (AT1R) tested by western blot; methylation of angiotensin II receptor 1b (AT1b) gene used pBLUE-T-cloning to check. The SBP and DBP in the offspring of renovascular hypertensive dams were higher than those in control group. Moreover, interstitial inflammatory infiltration was significant in the kidney and the protein expression of AT1R was also increased in the offspring of renovascular hypertensive dams. Conversely, methylation of AT1b promoter (U01033 277–1611) decreased in the first 3 CG sites. Either prenatal or postnatal treatment with H₂S could increase the methylation of AT1b and downregulate AT1R expression then improve the blood pressure. These results suggested that parental secondary hypertension-induced kidney damage that elevated basal blood pressure in adult offspring. Prenatal or postnatal administration with H₂S induced improved effect accompanied by an increased methylation of AT1b gene then downregulated protein of AT1R in offspring.

Although it is an essential nutrient, high choline intake directly or indirectly via its metabolite is associated with increased risk of cardiovascular disease, the mechanism of which remains to be elucidated. The present study was performed to investigate whether hydrogen sulfide (H₂S) was involved in high choline‐induced cardiac dysfunction and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS), the indicators of cardiac function measured by echocardiography, were significantly decreased in mice fed a diet containing 1.3% choline for 4 months as compared to the control, while applying 3,3‐dimethyl‐1‐butanol (DMB) to suppress trimethylamine N‐oxide (TMAO, a metabolite of choline) generation ameliorated the cardiac function. Subsequently, we found that feeding choline or TMAO significantly increased the protein levels of cyclic GMP‐AMP (cGAMP) synthase (cGAS), stimulator of interferon genes (STING), NOD‐like receptor protein 3 (NLRP3), caspase‐1, and interleukin‐1β (IL‐1β) as compared to the control, which indicated the activation of cGAS‐STING‐NLRP3 inflammasome axis. Moreover, the protein expression of cystathionine γ‐lyase (CSE), the main enzyme for H₂S production in the cardiovascular system, was significantly increased after dietary supplementation with choline, but the plasma H₂S levels were significantly decreased. To observe the effect of endogenous H₂S, CSE knockout (KO) mice were used, and we found that the EF, FS, and plasma H₂S levels in WT mice were significantly decreased after dietary supplementation with choline, while there was no difference between CSE KO + control and CSE KO + choline group. To observe the effect of exogenous H₂S, mice were intraperitoneally injected with sodium hydrosulfide (NaHS, a H₂S donor) for 4 months, and we found that NaHS improved the cardiac function and reduced the protein levels of cGAS, STING, NLRP3, caspase‐1, and IL‐1β in mice receiving dietary choline. In conclusion, our studies revealed that high choline diet decreased plasma H₂S levels and induced cardiac dysfunction via cGAS‐STING‐NLRP3 inflammasome axis while H₂S treatment could restore the cardiac function by inhibiting cGAS‐STING‐NLRP3 inflammasome axis.

The present study was performed to investigate whether H₂S could restore the diurnal variation in cardiac function of aging mice and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS) in 3‐month‐old mice exhibited diurnal variations over a 24‐hour period. However, the diurnal variations were disrupted in 18‐month‐old mice, and there was a decline in EF and FS. In addition, the plasma malondialdehyde (MDA) levels were increased, and H₂S concentrations and superoxide dismutase (SOD) activities were decreased in 18‐month‐old mice. Then, CSE KO mice were used to determine if there was a relationship between endogenous H₂S and diurnal variations in EF and FS. There was no difference in 12‐hour averaged EF and FS between dark and light periods in CSE KO mice accompanying increased MDA levels and decreased SOD activities in plasma, indicating that deficiency of endogenous H₂S blunted diurnal variations of cardiac function. To determine whether oxidative stress disrupted the diurnal variations in cardiac function, D‐galactose‐induced subacute aging mice were employed. After 3‐month D‐gal treatment, both 12‐hour averaged EF and FS in dark or light periods were decreased; meanwhile, there was no difference in 12‐hour averaged EF and FS between dark and light periods. After 3‐month NaHS treatment in the D‐gal group, the plasma MDA levels were decreased and SOD activities were increased. The EF and FS were lower during the 12‐hour light period than those during the 12‐hour dark period which was fit to sine curves in the D‐gal+NaHS group. Identical findings were also observed in 18‐month‐old mice. In conclusion, our studies revealed that the disrupted diurnal variation in cardiac function was associated with increased oxidative stress and decreased H₂S levels in aging mice. H₂S could restore the diurnal variation in cardiac function of aging mice by reducing oxidative stress.