Published online before print March 30, 2001, doi: 10.1161/hh0701.088842
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Ischemic Preconditioning Upregulates Vascular Endothelial Growth Factor mRNA Expression and Neovascularization via Nuclear Translocation of Protein Kinase C 
in the Rat Ischemic Myocardium
From the First Department of Internal Medicine (H. Kawata, A.K., H. Kurioka, E.T., Y.S., T.H., K.D.), Nara Medical University, Nara; Department of Forensic Medicine (K.-i.Y., K.H., M.K.), Graduate School of Medicine, University of Tokyo; and Department of Anatomy and Cell Biology (T.U.), Wakayama Medical College, Wakayama, Japan.
Correspondence to Ken-ichi Yoshida, MD, Department of Forensic Medicine, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail kyoshida{at}m-u.tokyo.ac.jp
Abstract—Ischemic
preconditioning (IP) exerts cardioprotection through protein kinase C
(PKC) activation, whereas myocardial ischemia enhances vascular
endothelial growth factor (VEGF) mRNA expression.
However, the IP effect or the involvement of PKC on the VEGF expression
is unknown in myocardial infarction. We investigated whether IP
enhances VEGF gene expression and angiogenesis through PKC activation
in the in vivo myocardial infarction model. Sprague-Dawley rats were
assigned into the following 3 groups: the sham group; the IP group,
which underwent 3 cycles of 3 minutes of ischemia and 5 minutes
of reperfusion (IP procedure); and the non-IP group. The latter 2
groups were subsequently subjected to left anterior descending
coronary artery occlusion. To examine the involvement of PKC,
the PKC inhibitor chelerythrine (5 mg/kg) or
bisindolylmaleimide (1 mg/kg) was injected intravenously
before the IP procedures. PKC
was translocated to the nucleus after
10 minutes of ischemia after the IP procedure but was not
translocated in the non-IP and the sham groups. VEGF mRNA expression 3
hours after infarction was significantly higher in the IP group than in
the non-IP and the sham groups. Capillary density in the infarction was
significantly higher, whereas the infarct size was smaller in the IP
group than in the non-IP group at 3 days of infarction. Chelerythrine
but not bisindolylmaleimide blocked all of the IP effects on the
nuclear translocation of PKC, enhancement of VEGF mRNA expression
and angiogenesis, and infarct size limitation. These results
show that IP may enhance VEGF gene expression and angiogenesis through
nuclear translocation of PKC in the infarcted
myocardium.
Key Words: angiogenesis • ischemic preconditioning • myocardial infarction • protein kinase C • vascular endothelial growth factor
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