Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats.
Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats.
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DOI：
10.1016/j.ejphar.2016.04.054
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发表时间：
2016-07-15
影响因子：
5
通讯作者：
Abdel-Rahman AA
中科院分区：
文献类型：
--
作者：
El-Sayed SS;Zakaria MN;Abdel-Ghany RH;Abdel-Rahman AA
胱硫醚-γ裂解酶（CSE）活性减弱（内源性H2S水平降低）与糖尿病高血压和心肌功能障碍有关。在这里，我们测试的假设，CSE衍生的H2S介导的心血管保护所赋予的咪唑啉I1受体激动剂莫索尼定在糖尿病大鼠模型。我们利用链脲佐菌素（STZ; 55 mg/kg i.p）诱导雄性Wistar大鼠糖尿病。4周后，STZ处理的大鼠接受载体、莫索尼定（2或6 mg/kg;管饲法）、CSE抑制剂DL-炔丙基甘氨酸（37.5mg/kg i.p）或DL-炔丙基甘氨酸与莫索尼定（6 mg/kg），持续3周。莫索尼定改善血糖状态，逆转STZ治疗大鼠的心肌肥厚、高血压和压力反射功能障碍。离体研究表明，STZ引起CSE表达/活性、H2S和一氧化氮（NO）水平和血清脂联素降低，心肌咪唑啉I1受体表达、p38和细胞外信号调节激酶、ERK 1/2、磷酸化和脂质过氧化（以丙二醛表示）升高。莫索尼定逆转这些生化反应，并抑制死亡相关蛋白激酶-3的表达。最后，药理学CSE抑制（DL-炔丙基甘氨酸）消除了莫索尼定引起的有利的心血管、血糖和生化反应。这些发现首次证明了CSE衍生的H2S在糖尿病大鼠模型中血糖控制和咪唑啉I1受体激活（莫索尼定）所产生的有利心血管效应中的机制作用。
Blunted cystathionine-γ lyase (CSE) activity (reduced endogenous H2S-level) is implicated in hypertension and myocardial dysfunction in diabetes. Here, we tested the hypothesis that CSE derived H2S mediates the cardiovascular protection conferred by the imidazoline I1 receptor agonist moxonidine in a diabetic rat model. We utilized streptozotocin (STZ; 55 mg/kg i.p) to induce diabetes in male Wistar rats. Four weeks later, STZ-treated rats received vehicle, moxonidine (2 or 6 mg/kg; gavage), CSE inhibitor DL-propargylglycine, (37.5 mg/kg i.p) or DL-propargylglycine with moxonidine (6 mg/kg) for 3 weeks. Moxonidine improved the glycemic state, and reversed myocardial hypertrophy, hypertension and baroreflex dysfunction in STZ-treated rats. Ex vivo studies revealed that STZ caused reductions in CSE expression/activity, H2S and nitric oxide (NO) levels and serum adiponectin and elevations in myocardial imidazoline I1 receptor expression, p38 and extracellular signal-regulated kinase, ERK1/2, phosphorylation and lipid peroxidation (expressed as malondialdehyde). Moxonidine reversed these biochemical responses, and suppressed the expression of death associated protein kinase-3. Finally, pharmacologic CSE inhibition (DL-propargylglycine) abrogated the favorable cardiovascular, glycemic and biochemical responses elicited by moxonidine. These findings present the first evidence for a mechanistic role for CSE derived H2S in the glycemic control and in the favorable cardiovascular effects conferred by imidazoline I1 receptor activation (moxonidine) in a diabetic rat model.