Reductions in hydrogen sulfide (HS) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N-nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and dysfunction. The cardioprotective effects of NaHS were counteracted by Gli which inhibited the Akt/eNOS/NO pathway. This suggests that the effects of hydrogen sulfide were mediated by the activation of the K channels. In conclusion, hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease via the activation of the Akt/eNOS/NO pathway, which was mediated by K channels. Impact statement 1. We found that HS ameliorated L-NAME-induced cardiac remodeling and dysfunction, and played a protective role in L-NAME-induced hypertensive heart disease, which the existing studies have not reported. 2. HS activated the Akt/eNOS/NO pathway, thereby playing a cardioprotective role in L-NAME-induced hypertensive heart disease. 3. The cardioprotective effect of HS was mediated by ATP-sensitive potassium channels.

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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.

Aim: To study the molecular mechanisms underlying α-tocopheryl succinate (α-TOS)-induced apoptosis in erbB2-positive breast cancer cells and to determine whether α-TOS and the human recombinant TNF-related apoptosis-inducing ligand (hrTRAIL) act synergically to induce cell death of erbB2-expressing breast cancer cells. Methods: The annexin V binding method was used to measure apoptosis induced by α-TOS and/or hrTRAIL. RT-PCR and Western blotting were performed to detect gene and protein expression. A colorimetric assay was performed to detect caspase activity. The TransAM TM NF-κB p65 kit was used to assess NF-κB activation. Results: α-TOS (100 μmol/L) significantly inhibited NF-κB nuclear translocation in erbB2-expressing breast cancer cells; this inhibition is expected to result in the inactivation of NF-κB. α-TOS (50 and 100 μmol/L) inhibited the expression of Flice-like inhibitory protein (FLIP) and cellular inhibitor of apoptosis protein 1 (c-IAP1) in erbB2-positive cells. α-TOS (100 μmol/L) inhibited Akt activation and augmented the activity of caspase 3 and caspase 8 in breast cancer cells expressing erbB2. α-TOS (50 μmol/L) and hrTRAIL (30 mg/mL) acted synergically to induce apoptosis in breast cancer cells. α-TOS also decreased the hrTRAIL-induced transient activation of NF-κB . Conclusion: Our results suggest that α-TOS mediates the apoptosis of erbB2-positive breast cancer cells and acts synergically with hrTRAIL via the NF-κB pathway.Keywords: erbB2; α-TOS; breast cancer; NF-κB; apoptosis; hrTRAIL Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1604Sinica ( -1610 doi: 10.1038/aps.2010 Original Article

Circadian rhythms are essential in a myriad of physiological processes to maintain homeostasis, especially the redox homeostasis. However, little is known about whether plasma H 2 S exhibits the physiological diurnal variation. The present study was performed to investigate the diurnal fluctuations of plasma H 2 S and explore the potential mechanisms. We found that the plasma H 2 S of the C57BL/6J mice was significantly higher at 19 o'clock than those at 7 o'clock which was not affected by the blood-collecting sequence and the concentrations of plasma cysteine (a precursor of H 2 S). No significant differences in mRNA or protein expression of the CSE, CBS, or MPST were observed between 7: 00 and 19: 00. There were also no significant differences in the CSE and CBS activities, while the activities of MPST in tissues were significantly higher at 19 o'clock. After treatment with AOAA (a CBS inhibitor) or PPG (a CSE inhibitor) for 14 days, plasma H 2 S concentrations at 19 o'clock were still significantly higher than those at 7 o'clock, although they were both significantly decreased as compared with controls. Identical findings were also observed in CSE KO mice. We also found the plasma H 2 O 2 concentrations were significantly higher at 19 o'clock than those at 7 o'clock. However, H 2 O 2 concentrations were significantly decreased at 19 o'clock than those at 7 o'clock when mice were exposed to continuous light for 24 h. Meanwhile, the diurnal fluctuations of plasma H 2 S levels and MPST activities in tissues were disappeared. After treatment with DTT for 14 days, there was no significant difference in plasma H 2 O 2 concentrations between 7 o'clock and 19 o'clock. Meanwhile, the diurnal fluctuations of plasma H 2 S levels and MPST activities in tissues were disappeared. Identical findings were also observed in SOD 2+/− mice. When heart tissues were incubated with increasing concentrations of H 2 O 2 in vitro, H 2 O 2 could dose-dependently increase the activity of MPST within a certain concentration range. In conclusion, our studies revealed that plasma H 2 S concentration and tissue MPST activity exhibited diurnal fluctuations. Modulated by plasma H 2 O 2 concentration, changes of MPST activity probably led to the diurnal fluctuations of plasma H 2 S.