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Adeno‐Sh Beta Catenin Abolishes Ischemic Preconditioning Mediated Cardioprotection by Downregulation of its Target Genes VEGF, Bcl‐2 & Survivin In Rat Myocardial Ischemia Model
Author(s) -
Thirunavukkarasu Mahesh,
Zhan Lijun,
Han Zhihua,
Me Venugopal P,
Maulik Nilanjana
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1140.11
Subject(s) - cardioprotection , survivin , downregulation and upregulation , angiogenesis , gsk3b , ischemic preconditioning , gene silencing , chemistry , ischemia , kinase , medicine , apoptosis , gsk 3 , gene , biochemistry
β‐catenin (β‐cat) is a downstream target of Glycogen Synthase Kinase‐3β (GSK‐3β) that plays a vital role in ischemic preconditioning (IP) mediated angiogenesis & cardioprotection. In the present study we investigated the mechanism of IP mediated cardioprotection through cytosolic β‐cat stabilization, nuclear translocation & activation of its target genes VEGF, Bcl‐2 & survivin. β‐cat expression was suppressed by intramyocardial injection of adenovirus associated sh‐RNA against β‐cat (Ad‐sh‐β‐cat, 4×10 8 pfu). Adeno‐LacZ was used as the control. The rats were assigned to four groups (1) Control‐IR (CIR) (2) Ad‐LacZ + IR (LIR) (3) Ad‐LacZ + IP (LIP) (4) Ad‐sh‐β‐cat + IP (sh‐β‐catIP). 72h after injection, isolated hearts were subjected to 30min of ischemia [I] & 2h of reperfusion [R] (IR). Designated hearts were subjected to IP (5min of I + 10min R, 4 cycles) before IR. Significant reduction in left ventricular functional recovery throughout reperfusion & increased infarct size were observed in sh‐β‐catIP compared to LIP. Real time PCR & RT‐PCR analysis showed significant downregulation of mRNA expression of VEGF, Bcl‐2 & survivin in sh‐β‐catIP compared to LIP. These findings indicated for the first time that silencing β‐cat abolished IP mediated cardioprotection, thereby validating that β‐cat activation & nuclear translocation is necessary for the IP mediated expression of VEGF, Bcl‐2 & survivin.