title: Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models.
abstract: Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69 ± 5.8 % (n = 11) to 40 ± 6.5 % (n = 12), P = 0.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62 ± 7.6 % controls, n = 10, versus 61 ± 6.9 % rIPC after cyanamide, n = 10, P > 0.05). (ii) In a forearm plethysmography model of endothelial ischaemia-reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia-reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine (P = 0.9), but rIPC failed to protect carriers of Glu504Lys polymorphism (P = 0.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600 mg od or placebo for 48 h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18 ± 1.03 % and 4.76 ± 0.93 % P = 0.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87 ± 1.27 % and 3.05 ± 0.53 %, P = 0.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Hussain
authors.initials: H
authors.lastname: Contractor
authors.forename: Nicolaj B
authors.initials: NB
authors.lastname: Støttrup
authors.forename: Colin
authors.initials: C
authors.lastname: Cunnington
authors.forename: Cedric
authors.initials: C
authors.lastname: Manlhiot
authors.forename: Jonathan
authors.initials: J
authors.lastname: Diesch
authors.forename: Julian O M
authors.initials: JO
authors.lastname: Ormerod
authors.forename: Rebekka
authors.initials: R
authors.lastname: Jensen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
authors.forename: Andrew
authors.initials: A
authors.lastname: Redington
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schmidt
authors.forename: Houman
authors.initials: H
authors.lastname: Ashrafian
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kharbanda
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000704:Analysis of Variance; D000818:Animals; D018592:Cross-Over Studies; D003484:Cyanamide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004221:Disulfiram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply*; D005838:Genotype; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D016014:Linear Models; D009154:Mutation; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D010991:Plethysmography; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D003484:Cyanamide; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D004221:Disulfiram