Urinary trypsin inhibitors afford cardioprotective effects through activation of PI3K-Akt and ERK signal transduction and inhibition of p38 MAPK and JNK.
BACKGROUND
We determined the effect of urinary trypsin inhibitors (UTI) in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases such as phosphatidylinositol-3-OH kinases (PI3K)-Akt and extracellular signal-regulated kinases (ERK 1/2) and apoptotic kinases such as p38 and JNK.


METHODS
The rats were anesthetized and subjected to an I/R insult consisting of 30-min left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size was measured after 120 min of reperfusion. UTI was given alone or along with wortmannin (inhibitor of PI3K) or PD098059 (inhibitor of ERK1/2) before LAD occlusion. The phosphorylation of Akt, ERK1/2, p38 and JNK was determined by immunoblotting after 5 min of reperfusion. UTI was administered 10 min before LAD occlusion, and wortmannin and PD098059 were administered 20 min before LAD occlusion.


RESULTS
UTI significantly reduced the infarct size compared with the control. Wortmannin or PD098059 alone did not affect the infarct size, but they abolished the UTI-induced cardioprotective effect. UTI significantly reduced the phosphorylation of p38 and JNK, while it enhanced that of Akt and ERK1/2.


CONCLUSIONS
UTI has a protective effect against regional myocardial I/R injury through activation of survival kinases PI3K-Akt and ERK1/2 and attenuation of p38 and JNK.
Kim
Seok J
SJ
Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea.
Yoo
Kyung Y
KY
Jeong
Cheol W
CW
Kim
Woong M
WM
Lee
Hyung K
HK
Bae
Hong B
HB
Kwak
Sang H
SH
Li
Mei
M
Lee
JongUn
J
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014361:Trypsin Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D006023:Glycoproteins; D014361:Trypsin Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C028665:urinastatin