We examined our hypothesis that (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (
CKD712) inhibits apoptosis in
myocardial ischemia and reperfusion (I/R) injury in vivo via activation of the
phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by reducing
inflammation during I/R. To do this, we induced a 30-min period of
ischemia by occlusion of the left anterior descending coronary artery of the rat followed by a 2-h (for phosphorylation of Akt), 6-h (for biochemical analysis), or 24-h (for functional analysis) period of reperfusion to determine the effect of
CKD712 treatment. Pretreatment with
CKD712 significantly improved myocardial function as evidenced by an increase in the +/-dP/dt and a decrease in the
infarct size, which were antagonized by a PI3K inhibitor,
wortmannin (WT). Interestingly,
CKD712 increased the phosphorylation of Akt and
cAMP-response element-binding protein and increased the expression of the Bcl-2 gene, but it reduced the expression of the Bax gene.
CKD712 decreased not only the expression but also the activity of the
caspase-3 protein in the myocardium after reperfusion. Thus, all of the antiapoptotic effects of
CKD712 were significantly inhibited by WT. Furthermore, the antiapoptotic effects of
CKD712 and its inhibition by WT in myocardium after reperfusion were confirmed by
terminal deoxynucleotidyl transferase-mediated
deoxyuridine triphosphate nick-end labeling staining. Finally,
CKD712 was found to reduce the serum levels of the high-mobility group box 1
protein,
tumor necrosis factor-alpha, and the cardiac
troponin I protein in addition to tissue levels of
malondialdehyde and
myeloperoxidase activity in I/R hearts. Taken together, both the activation of PI3K/Akt and its anti-inflammatory action prevent apoptosis in myocardial I/R injury by
CKD712.