title: Hydrophilic bile salt ursodeoxycholic acid protects myocardium against reperfusion injury in a PI3K/Akt dependent pathway.
abstract: The opening of mitochondrial permeability transition pore (PTP) during reperfusion injury of heart has been well demonstrated and thus controlling PTP would attenuate the myocardial damage and cell death. Ursodeoxycholic acid (UDCA) is a hydrophilic bile salt and has been shown to prevent apoptosis in hepatocytes by inhibiting the opening of PTP. Here we demonstrate the role of UDCA in preventing the reperfusion injury of heart through its ability to inhibit PTP. Wistar rats underwent 30 min left coronary artery occlusion (LCA) followed by 180 min reperfusion after treatment with 40 mg/kg per iv infusion of UDCA over 30 min before LCA occlusion. Other groups of rats were treated with PTP agonist atractyloside(5 mg/kg) or PI3 kinase inhibitor wortmannin (16 ug/kg) before UDCA treatment. UDCA treatment prior to LCA occlusion, activated phosphorylation of Akt and Bad. Phosphorylating Bad prevented its translocation in to mitochondria, there by preventing the down regulation of Bcl-2 expression and PTP opening. This was confirmed by reduced cytochrome C release from intramitochondrial space in to the cytosol and hence reduced cell death either by apoptosis (4.8 vs 11.8%, P<0.001, UDCA treated against control group) or necrosis (reduced MI area in UDCA treated group (22.1%) compared to control group(46.4%), P<0.001). In contrast, inhibition of Akt activation with PI3K inhibitor wortmannin or opening the PTP with atractyloside abolished, UDCA mediated cytoprotective effects. Studies on primary culture cardiomyocytes also confirmed our in vivo results of UDCA on cell survival. These results altogether demonstrate that UDCA protect the heart against reperfusion injury by inhibiting the PTP in a PI3K/Akt dependent pathway.
authors.affiliation: Department of Cardiovascular Surgery and Regeneration Technology, Oko, Nankoku, Kochi, Japan. rajesh@med.kochi-u.ac.jp
authors.forename: Katare Gopalrao
authors.initials: KG
authors.lastname: Rajesh
authors.forename: Ryoko
authors.initials: R
authors.lastname: Suzuki
authors.forename: Hironori
authors.initials: H
authors.lastname: Maeda
authors.forename: Murio
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Xing
authors.initials: X
authors.lastname: Yutong
authors.forename: Shiro
authors.initials: S
authors.lastname: Sasaguri
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001278:Atractyloside / Q000494:pharmacology; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008933:Mitochondrial Swelling / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014580:Ursodeoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology; D000077191:Wortmannin; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000730:Androstadienes; C494821:Bad protein, rat; D051025:bcl-Associated Death Protein; D001278:Atractyloside; D014580:Ursodeoxycholic Acid; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen; D000077191:Wortmannin