Mechanism of attenuation of diabetes mellitus and hypercholesterolemia induced vascular endothelial dysfunction by protein tyrosine phosphatase inhibition.
The study has been designed to investigate downstream mechanisms in the PTPase inhibition mediated attenuation of diabetes mellitus and hypercholesterolemia-induced vascular endothelial dysfunction. Diabetes mellitus was induced in rats using streptozotocin (55 mg/kg, i.v. once), while hypercholesterolemia was produced by feeding high cholesterol diet. After 4 weeks of streptozotocin and Cholesterol rich diet administration, vascular endothelium dysfunction was assessed, in terms of attenuation of acetylcholine-induced, endothelium-dependent relaxation (Isolated Aortic Ring Preparation), a decrease in serum nitrate/nitrite level, as well as mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). After 14 days of daily administration, sodium orthovanadate (8 mg/kg, p.o., 16 mg/kg, p.o and 24 mg/kg, p.o) and atorvastatin (30 mg/kg, p.o) (positive control) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and maintained integrity of vascular endothelium. However, this ameliorative effect of SOV was significantly blocked by UCN-01, (PDK inhibitor) and L-NAME (Inhibitor of eNOS). Therefore, it may be concluded that sodium orthovanadate, a specific inhibitor of PTPase, may stimulate PDK and eNOS and consequently improve vascular endothelium dysfunction. Thus, inhibition of PTPase might be a useful approach in the therapeutics of vascular endothelium dysfunction.
Department of Pharmacology, ISF College of Pharmacy, Ferozpur Road, Moga-142001, Punjab, India. ssm.research@gmail.com
Saurabh
S
Sharma
Manjeet
M
Singh
Pyare Lal
PL
Sharma
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D014638:Vanadates / Q000008:administration & dosage / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D011758:Pyrroles; D012333:RNA, Messenger; D014638:Vanadates; D013311:Streptozocin; D000069059:Atorvastatin; D017027:Protein Tyrosine Phosphatases; D000109:Acetylcholine