Effects of aprotinin on gene expression and protein synthesis after ischemia and reperfusion in rats.
BACKGROUND
Reperfusion injury of ischemic myocardium has been attributed to neutrophil infiltration, inflammatory activation and cardiac necrosis/apoptosis. Serine protease inhibition with aprotinin is cardioprotective, but the mechanism is unknown.


RESULTS
We studied aprotinin in a rat model of myocardial ischemia for 20 minutes and reperfusion for 20 minutes, 8 hours or 24 hours. Aprotinin (20,000 IU/kg) given 5 minutes before reperfusion significantly reduced leukocyte accumulation (P<0.01), myocardial injury (determined by CK depletion, P<0.01) and myocyte apoptosis (P<0.05) compared with vehicle treated rats. Differential gene expression analysis showed myocardial ischemia plus reperfusion increased expression of proinflammatory genes like P-selectin, E-selectin, intercellular adhesion molecule, tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6, monocyte chemoattractant protein-1, p53, and Fas (CD59). Aprotinin before reperfusion suppressed expression of these inflammatory genes. Finally, differential protein expression analysis demonstrated increased intercellular adhesion molecule-1, tumor necrosis factor-alpha, and p53 after myocardial ischemia plus reperfusion, and this effect was diminished by aprotinin.


CONCLUSIONS
We demonstrated myocardial ischemia plus reperfusion induced leukocyte accumulation, inflammation, gene expression, protein expression and finally tissue injury and showed aprotinin limiting reperfusion injury through each of these stages, even after 24 hours of reperfusion. This effect seems partly attributable to suppression of proinflammatory genes and leukocyte accumulation. This work casts further light on the complex signaling of ischemia and reperfusion.
Buerke
Michael
M
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle/Saale, Germany. michael.buerke@medizin.uni-halle.de
Pruefer
Diethard
D
Sankat
Dennis
D
Carter
Justin M
JM
Buerke
Ute
U
Russ
Martin
M
Schlitt
Axel
A
Friedrich
Ivar
I
Börgermann
Jochen
J
Vahl
Christian F
CF
Werdan
Karl
K
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D015425:Myocardial Reperfusion / Q000379:methods; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D051381:Rats
D007611:Aprotinin