Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 46, Issue 2, Pages 193-200Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2008.10.021
Keywords
PTEN; Ischemia-reperfusion injury; Infarct size; Apoptosis; Inducible gene targeting
Categories
Funding
- NIH [HL70079, HL080111, HL062311]
- National Research Service Award (NRSA) Institutional Training [T32 HD07549]
- American Heart Association
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PTEN is a dual lipid and protein phosphatase that antagonizes PI3K as well as other signaling pathways and regulates cellular survival and growth. However, its potential role in cardiac ischemia/reperfusion injury remains unknown. We established a transgenic mouse model with inducible and cardiac specific deletion of Pten gene (Pten(CKO)) in adult heart via tamoxifen dependent Cre-loxP mediated DNA recombination. 3 weeks after tamoxifen induced PTEN inactivation, elevated PI3K activity was observed in the Pten(CKO) hearts as determined from downstream AI(T signaling. No significant differences in cardiac function as well as chamber size were observed between Pten(CKO) and Control animals based on echocardiography. In response to 30 min ischemia followed by 120 min reperfusion in Lingendorff preparations, Pten(CKO) hearts developed significantly better function recovery than Control animals. At 60 min post reperfusion, the recovery of LVDP reached 77.9% of pre-ischemia basal in Pten(CKO) hearts vs 44.2% of Control (p<0.01). Consistent with the observed functional improvement, TTC staining revealed a significant reduction in infarct size in Pten(CKO) hearts compared with Control (24.2% vs 39.7%, p<0.05). Pten(CKO) hearts had significantly fewer apoptosis positive cardiomyrocytes after I/R injury as identified by TUNEL staining. Furthermore, ERK activity and BCL-2 expression were not affected at basal but became significantly higher after ischemia/reperfusion in Pten(CKO) hearts. These data indicate that PTEN may play a role in ischemia/reperfusion injury by inhibiting antiapoptotic survival signals. Inhibiting PTEN may serve as a potential approach to exert cardiac protection against ischemia reperfusion injury. (C) 2008 Elsevier Inc. All rights reserved.
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