title: Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats.
abstract: 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; 55mg/kg i.p) to induce diabetes in male Wistar rats. Four weeks later, STZ-treated rats received vehicle, moxonidine (2 or 6mg/kg; gavage), CSE inhibitor DL-propargylglycine, (37.5mg/kg i.p) or DL-propargylglycine with moxonidine (6mg/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.
authors.affiliation: Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address: shamy_samy84@yahoo.com.
authors.forename: Shaimaa S
authors.initials: SS
authors.lastname: El-Sayed
authors.affiliation: Department of Pharmacology and Toxicology, Zagazig University, Zagazig, Egypt.
authors.forename: Mohamed N M
authors.initials: MN
authors.lastname: Zakaria
authors.affiliation: Department of Pharmacology and Toxicology, Zagazig University, Zagazig, Egypt.
authors.forename: Rasha H
authors.initials: RH
authors.lastname: Abdel-Ghany
authors.affiliation: Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address: abdelrahmana@ecu.edu.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006984:Hypertrophy / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D052242:Adiponectin; D000480:Alkynes; D001786:Blood Glucose; D002316:Cardiotonic Agents; D007093:Imidazoles; C009055:propargylglycine; C043482:moxonidine; D003542:Cystathionine gamma-Lyase; D005998:Glycine; D006862:Hydrogen Sulfide
keywords: Cystathionine-γ lyase; DL-propargylglycine (PubChem CID: 95575); Diabetes; Hydrogen Sulfide; Hypertension; Imidazoline I(1) receptor, moxonidine; Myocardial dysfunction; moxonidine (PubChem CID: 4810); streptozotocin (PubChem CID: 29327)