title: Characterization of Angiotensin-(1-7) effects on the cardiovascular system in an experimental model of type-1 diabetes.
abstract: Although exogenous administration of Angiotensin-(1-7) [Ang-(1-7)] can prevent development of diabetes induced end-organ damage, little is known about the role of endogenous Ang-(1-7) in diabetes and requires further characterization. Here, we studied the effects of chronically inhibiting endogenous Ang-(1-7) formation with DX600, a selective angiotensin converting enzyme-2 (ACE2) inhibitor, on renal and cardiac NADPH oxidase (NOX) activity, vascular reactivity and cardiac function in a model of Type-1 diabetes. The contribution of endogenous Ang-(1-7) to the protective effects of Losartan and Captopril and that of prostaglandins to the cardiovascular effects of exogenous Ang-(1-7) were also examined. Cardiac and renal NOX activity, vascular reactivity to endothelin-1 (ET-1) and cardiac recovery from ischemia/reperfusion (I/R) injury were evaluated in streptozotocin-treated rats. Chronic treatment with DX600 exacerbated diabetes-induced increase in cardiac and renal NOX activity. Diabetes-induced abnormal vascular reactivity to ET-1 and cardiac dysfunction were improved by treatment with Ang-(1-7) and worsened by treatment with DX600 or A779, a Mas receptor antagonist. Ang-(1-7)-mediated improvement in cardiac recovery or vascular reactivity was attenuated by Indomethacin. Captopril and Losartan-induced improvement in cardiovascular function was attenuated when these drugs were co-administered with A779. Ang-(1-7)-mediated decrease in renal NOX activity was prevented by indomethacin. Losartan also decreased renal NOX activity that could be attenuated with A779 co-treatment. In conclusion, endogenous Ang-(1-7) inhibits diabetes-induced cardiac/renal NOX activity and end-organ damage, and mediates the actions of Captopril and Losartan. Further, prostaglandins are important intermediaries in the beneficial effects of Ang-(1-7) in diabetes. Combining either Losartan or Captopril with Ang-(1-7) had additional beneficial effects in preventing diabetes-induced cardiac dysfunction and this may represent a novel therapeutic strategy. Collectively, these data shed new insights into the likely mechanism of action through which the ACE2/Ang-(1-7)/Mas receptor axis prevents Type 1 diabetes-induced cardiovascular dysfunction.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait.
authors.forename: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.forename: Gursev S
authors.initials: GS
authors.lastname: Dhaunsi
authors.forename: Batoul M
authors.initials: BM
authors.lastname: Makki
authors.forename: Bedour A
authors.initials: BA
authors.lastname: Qabazard
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: C092006:7-Ala-angiotensin (1-7); C556151:DX600 peptide; D019332:Endothelin-1; D010446:Peptide Fragments; D010455:Peptides; D011453:Prostaglandins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D002216:Captopril; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D019808:Losartan