Document Detail


Genetically determined angiotensin converting enzyme level and myocardial tolerance to ischemia.
MedLine Citation:
PMID:  20667972     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene and displaying an ACE level range similar to humans. Infarct size in ACE1c was 29% lower than in ACE2c (P<0.05). Pretreatment with a kinin B2 receptor antagonist suppressed this reduction. In ACE3c, infarct size was the same as in ACE2c. But ischemic preconditioning, which reduced infarct size in ACE2c (-63%, P<0.001) and ACE1c (-52%, P<0.05), was not efficient in ACE3c (-2%, NS, P<0.01 vs. ACE2c). In ACE3c, ischemic preconditioning did not decrease myocardial inflammation or cardiomyocyte apoptosis. Pretreatment with a renin inhibitor had no cardioprotective effect in ACE2c, but in ACE3c partially restored (38%) the cardioprotection of ischemic preconditioning. Thus, a modest genetic increase in ACE impairs myocardial tolerance to ischemia. ACE level plays a critical role in cardiac ischemia, through both kinin and angiotensin mediated mechanisms.
Authors:
Erij Messadi; Marie-Pascale Vincent; Violaine Griol-Charhbili; Chantal Mandet; Juliana Colucci; John H Krege; Patrick Bruneval; Nadine Bouby; Oliver Smithies; François Alhenc-Gelas; Christine Richer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-28
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  24     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-02     Completed Date:  2011-01-04     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4691-700     Citation Subset:  IM    
Affiliation:
INSERM U872, Centre de Recherche des Cordeliers, Paris, France.
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MeSH Terms
Descriptor/Qualifier:
Amides / pharmacology
Angiotensin I / pharmacology
Angiotensin II / pharmacology
Animals
Apoptosis / drug effects
Blood Pressure / drug effects
Bradykinin / analogs & derivatives,  pharmacology
Fumarates / pharmacology
Heart / drug effects*
Kinins / pharmacology
Lung / enzymology
Mice
Mice, Mutant Strains
Myocardial Infarction / enzymology*,  genetics
Myocardial Ischemia / enzymology*,  genetics
Myocardium / enzymology*
Peptidyl-Dipeptidase A / genetics,  metabolism*
Receptors, Bradykinin / antagonists & inhibitors
Renin / antagonists & inhibitors
Reperfusion Injury / genetics*
Grant Support
ID/Acronym/Agency:
R01 HL049277/HL/NHLBI NIH HHS; R01 HL049277-16/HL/NHLBI NIH HHS; R01 HL049277-17/HL/NHLBI NIH HHS; R01 HL049277-18/HL/NHLBI NIH HHS; R01 HL049277-19/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Amides; 0/Fumarates; 0/Kinins; 0/Receptors, Bradykinin; 11128-99-7/Angiotensin II; 502FWN4Q32/aliskiren; 58-82-2/Bradykinin; 7PG89G35Q7/icatibant; 9041-90-1/Angiotensin I; EC 3.4.15.1/Peptidyl-Dipeptidase A; EC 3.4.23.15/Renin
Comments/Corrections

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