INHIBITION OF p53 BY PIFITHRIN-alpha REDUCES MYOCYTE APOPTOSIS AND LEUKOCYTE TRANSMIGRATION IN AGED RAT HEARTS FOLLOWING 24 HOURS OF REPERFUSION.

Authors: Liu, P  Xu, B  Cavalieri, TA  Hock, CE 
Citation: Liu P, etal., Shock. 2008 Feb 28;.
Pubmed: (View Article at PubMed) PMID:18317410
DOI: Full-text: DOI:10.1097/SHK.0b013e31816a192d

Ischemic heart disease is a common age-related disease. Apoptotic cell death and inflammation are the major contributors to I/R injury. The mechanisms that trigger myocyte apoptosis and inflammation during myocardial I/R (MI/R) remain to be elucidated. Published data from our laboratory demonstrated that pretreatment of MI/R rats with pifithrin-alpha (PFT), a specific p53 inhibitor, reduced myocyte apoptosis and improved cardiac function compared with MI/R rats pretreated with saline at 4 h of reperfusion. In the present study, we investigated the effects of PFT on the occurrence of myocyte apoptosis and leukocyte transmigration in the later period of reperfusion. Aged (20-month-old) male F344 ratswere subjected to 30 min of myocardial ischemia via ligature of the LCA, followed by 24 h of reperfusion. Pifithrin-alpha (2.2 mg/kg, intraperitoneally) or saline was administered to rats before ischemia. The results indicate that pretreatment of MI/R rats with PFT significantly decreased the percentage of infarct area to ischemic area (33 +/- 8 vs. 54 +/- 9, P < 0.05) and improved cardiac output (79 +/- 11 vs. 38 +/- 9 mL/min per 100 g body weight, P < 0.05) when compared with rats pretreated with saline at 24 h of reperfusion. The protective effects of PFT may involve the p53/Bax-mediated apoptosis because treatment of MI/R rats with PFT attenuated the ratio of Bax to Bcl2 (0.97 +/- 0.1 vs. 2.1 +/- 0.2, P < 0.05) and reduced myocyte apoptosis. Interestingly, inhibition of p53 transcriptional function by PFT alleviated leukocyte infiltration into the ischemic area of the heart (339 +/- 37 vs. 498 +/- 75 cells/10 high-power fields, P < 0.05). These data suggest that inhibition of p53 transcriptional function by PFT attenuates myocyte apoptosis and alleviates leukocyte transmigration at 24 h of reperfusion. The mechanisms by which p53 modulates leukocyte transmigration require further investigation.

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RGD Object Information
RGD ID: 2290554
Created: 2008-03-19
Species: All species
Last Modified: 2008-03-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.