Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

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• 作者：Shaimaa S. El-Sayed^a ; ¹ ; ^{shamy_samy84@yahoo.com" class="auth_mail" title="E-mail the corresponding author} ; Mohamed N.M. Zakaria^b ; Rasha H. Abdel-Ghany^b ; Abdel A. Abdel-Rahman^a ; ^{abdelrahmana@ecu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：LV+dp/dtmax ; Maximum rate of left ventricle pressure rise ; BGL ; Blood glucose level ; BP ; Blood pressure ; BRS ; Baroreflex sensitivity ; CSE ; Cystathionine-γ-lyase ; DAPK3 ; Death associated protein kinase-3 ; ERK ; Extracellular signal-regulated kinase ; HR ; Heart rate ; HW/BW ; Heart weight/Body weight ; MAP ; Mean arterial pressure ; MAPK ; Mitogen activated protein kinase ; OGTT ; Oral glucose tolerance test ; SHR ; Spontaneously hypertensive rats ; STZ ; Streptozotocin
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：783
• 期：Complete
• 页码：73-84
• 全文大小：5264 K

文摘

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.