Mechanisms of apoptosis after ischemia and reperfusion: role of the renin-angiotensin system.
BACKGROUND
Apoptosis plays a key role in the pathogenesis of cardiac diseases. We examined the influence of the renin-angiotensin system (RAS) on different regulators of apoptosis using an isolated hemoperfused working porcine heart model of acute ischemia (2 h), followed by reperfusion (4 h).


RESULTS
23 porcine hearts were randomized to 5 groups: hemoperfused non-infarcted hearts (C), infarcted hearts (MI: R. circumflexus), infarcted hearts treated with quinaprilat (Q), infarcted hearts treated with angiotensin-I (Ang I), and infarcted hearts treated with angiotensin-I and quinaprilat (QA). Fas, Bax, bcl-2 and p53 proteins were increased in MI hearts and further elevated by Ang I. Quinaprilat reduced Bax and p53. Bcl-2 was elevated in Q and reduced in QA. An early upregulation of caspase-3 gene and protein expression was detected in MI and Ang I hearts compared to C. Q reduced caspase-3 gene expression, but had no effect on caspase-3 and Fas protein.


CONCLUSIONS
These data suggest that the RAS plays a pivotal role in cardiac apoptosis which is the early and predominant form of death in myocardial infarction. Ischemia/reperfusion induces programmed cell death via extrinsic and intrinsic pathways. Early treatment with quinaprilat attenuated cardiomyocyte apoptosis.
Institute of Clinical Pharmacology and Toxicology, Charité-University Medicine Berlin, Benjamin Franklin Campus, Berlin, Germany.
P
P
Kossmehl
E
E
Kurth
S
S
Faramarzi
B
B
Habighorst
M
M
Shakibaei
M
M
Wehland
R
R
Kreutz
M
M
Infanger
A H
AH
J Danser
J
J
Grosse
M
M
Paul
D
D
Grimm
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D048430:Cell Shape; D005260:Female; D006321:Heart / Q000502:physiology*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D012084:Renin-Angiotensin System / Q000502:physiology*; D015427:Reperfusion Injury; D013552:Swine; D044005:Tetrahydroisoquinolines / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D000804:Angiotensin II; C054501:quinaprilat; D000803:Angiotensin I; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3