Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models.
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 [6...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Jezik: | English |
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2013
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| _version_ | 1826270158712209408 |
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| author | Contractor, H Støttrup, N Cunnington, C Manlhiot, C Diesch, J Ormerod, J Jensen, R Bøtker, H Redington, A Schmidt, MR Ashrafian, H Kharbanda, R |
| author_facet | Contractor, H Støttrup, N Cunnington, C Manlhiot, C Diesch, J Ormerod, J Jensen, R Bøtker, H Redington, A Schmidt, MR Ashrafian, H Kharbanda, R |
| author_sort | Contractor, H |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:36:27Z |
| format | Journal article |
| id | oxford-uuid:466f496e-f345-4db8-a842-33bb5c2b1567 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:36:27Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:466f496e-f345-4db8-a842-33bb5c2b15672022-03-26T15:13:38ZAldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:466f496e-f345-4db8-a842-33bb5c2b1567EnglishSymplectic Elements at Oxford2013Contractor, HStøttrup, NCunnington, CManlhiot, CDiesch, JOrmerod, JJensen, RBøtker, HRedington, ASchmidt, MRAshrafian, HKharbanda, RMitochondrial 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. |
| spellingShingle | Contractor, H Støttrup, N Cunnington, C Manlhiot, C Diesch, J Ormerod, J Jensen, R Bøtker, H Redington, A Schmidt, MR Ashrafian, H Kharbanda, R Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. |
| title | Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. |
| title_full | Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. |
| title_fullStr | Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. |
| title_full_unstemmed | Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. |
| title_short | Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. |
| title_sort | aldehyde dehydrogenase 2 inhibition blocks remote preconditioning in experimental and human models |
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