title: Angiotensin type I receptor blockade in conjunction with enhanced Akt activation restores coronary collateral growth in the metabolic syndrome.
abstract: We have previously demonstrated that Akt was required for repetitive ischemia (RI)-induced coronary collateral growth (CCG) in healthy rats but was not activated by RI in the metabolic syndrome (JCR:LA-cp rats) where CCG was impaired. Here we hypothesized that failure of angiotensin type I receptor (AT₁R) blockers to restore Akt activation is a key determinant of their inability to completely restore CCG in the metabolic syndrome. Therefore, we investigated whether adenovirus-mediated delivery of constitutively active Akt (MyrAkt-Adv) in conjunction with AT₁R blockade (candesartan) was able to restore RI-induced CCG in JCR:LA-cp rats. Successful myocardial MyrAkt-Adv delivery was confirmed by a >80% transduction efficiency and an approximately fourfold increase in Akt expression and activation. CCG was assessed by myocardial blood flow measurements in the normal and collateral-dependent zones. MyrAkt-Adv alone significantly increased RI-induced CCG in JCR:LA-cp rats (~30%), but it completely restored CCG in conjunction with administration of candesartan. In contrast, dominant negative Akt (DN-Akt-Adv) reversed the beneficial effect of candesartan on CCG in JCR:LA-cp rats. We conclude that optimal restoration of coronary collateral growth in JCR:LA-cp rats requires a combination of AT₁R blockade with constitutive Akt activation. These findings may carry implications for metabolic syndrome patients in need of coronary revascularization.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, Mobile, AL 36688, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Jadhav
authors.forename: Tracy
authors.initials: T
authors.lastname: Dodd
authors.forename: Erika
authors.initials: E
authors.lastname: Smith
authors.forename: Erin
authors.initials: E
authors.lastname: Bailey
authors.forename: Angelo L
authors.initials: AL
authors.lastname: Delucia
authors.forename: James C
authors.initials: JC
authors.lastname: Russell
authors.forename: Rowan
authors.initials: R
authors.lastname: Madison
authors.forename: Barry
authors.initials: B
authors.lastname: Potter
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D003097:Collateral Circulation / Q000187:drug effects* / Q000502:physiology; D003331:Coronary Vessels / Q000254:growth & development* / Q000502:physiology; D004195:Disease Models, Animal; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D051057:Proto-Oncogene Proteins c-akt; C081643:candesartan