Liu, P., Xu, B., Cavalieri, T. A. & Hock, C. E. Pifithrin- attenuates p53-mediated apoptosis and improves cardiac function in response to myocardial ischemia/reperfusion in aged rats. Shock 26, 608-614

Department of Cell Biology, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, 2 Medical Center Drive, Stratford, NJ 08084, U.S.A.
Shock (Impact Factor: 3.05). 01/2007; 26(6):608-14. DOI: 10.1097/
Source: PubMed


Ischemic cardiovascular disease is a common age-related disease. The p53-dependent cardiac myocyte apoptosis induced by myocardial ischemia/reperfusion (MI/R) is an important feature in the progression of ischemic heart disease. In the present studies, we hypothesized that inhibition of p53-dependent myocyte apoptosis may improve cardiac dysfunction in aged rats after MI/R. A dose (2.2 mg/kg, i.p.) of pifithrin-alpha (PFT), a p53 inhibitor, or saline was administered to 20-month-old male F344 rats, which were subjected to 30 min of myocardial ischemia by ligating the left main coronary artery, followed by release of the ligature and 4 h of reperfusion. Results of our experiments indicate that MI/R induced a significant decrease in cardiac output index (CI) and mean arterial blood pressure (MABP). Administration of PFT to aged rats 40 min before ischemia significantly improved CI and MABP during 3 to 4 h of reperfusion. The improvement of cardiac function was associated with a marked reduction in DNA fragmentation in the area at risk of the heart when compared with aged MI/R rats pretreated with saline. Interestingly, treatment with PFT 10 min after ischemia or 10 min after reperfusion had a similar protective effect on CI and MABP, but this effect did not reach statistical significance when compared with aged MI/R rats pretreated with saline. Treatment with PFT, however, did not influence plasma creatine kinase activity and the number of circulating leukocytes and infiltrated leukocytes in the area at risk of the heart. Moreover, results of Western blot show that pretreatment with PFT significantly attenuated the ratio of Bax to Bcl-2 in the area-at-risk tissue of the heart compared with that of rats pretreated with saline. Our results suggest that pretreatment with PFT significantly improved cardiac function. The mechanism of protective effect of PFT may involve the inhibition of p53 transcriptional function, thereby attenuating the p53/Bax-mediated myocyte apoptosis during the reperfusion period.

6 Reads
  • Source
    • "AngII (200 ng/kg/min, Sigma-Aldrich) was continuously administered to mice for 2 weeks by Alzet micro-osmotic pumps (DURECT Corporation) implanted subcutaneously [10]. PFT-α (Sigma-Aldrich) was dissolved in dimethyl sulfoxide (DMSO), and the dilution was injected into mice intraperitoneally with a 3.0 mg/kg dose one day [11] before AngII infusion and then was injected in a similar dose once every 3 days during AngII infusion. At the end of experiments, mice were subjected to the echocardiography, noninvasive blood pressure (NIBP) measurements and analyses for myocardial immunohistochemistry and Western blot. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiotensin II (AngII) is a major contributor to the development of heart failure, however, the molecular and cellular mechanisms still remain elucidative. Inadequate angiogenesis in myocardium leads to transition from cardiac hypertrophy to dysfunction, this study was therefore conducted to examine the effects of AngII on myocardial angiogenesis and the underlying mechanisms. AngII treatment significantly impaired angiogenetic responses, which were determined by counting the capillaries either in matrigel formed by cultured cardiac microvascular endothelial cells (CMVECs) or in myocardium of mice and by measuring the in vitro and in vivo production of VEGF proteins, and stimulated accumulation and phosphorylation of cytosolic p53 which led to increases in phosphorylated p53 and decreases of hypoxia inducible factor (Hif-1) in nucleus. All of these cellular and molecular events induced by AngII in CEMCs and hearts of mice were largely reduced by a p53 inhibitor, pifithrin-α (PFT-α). Interestingly, AngII stimulated the upregulation of Jagged1, a ligand of Notch, but it didn't affect the expression of Delta-like 4 (Dll-4), another ligand of Notch. Inhibition of p53 by PFT-α partly abolished this effect of AngII. Further experiments showed that knockdown ofJagged1 by addition of siRNA to cultured CMVECs dramatically declined AngII-stimulated accumulation and phosphorylation of p53 in cytosol, upregulation of phosphorylated p53 and downregulation of Hif-1 expression in nucleus, decrease of VEGF production and impairment of capillary-like tube formation by the cells. Our data collectively suggest that AngII impairs myocardial angiogenetic responses through p53-dependent downregulation of Hif-1 which is regulated by Jagged1/Notch1 signaling.
    PLoS ONE 10/2013; 8(10):e76529. DOI:10.1371/journal.pone.0076529 · 3.23 Impact Factor
  • Source
    • "To address the relative contribution of UV irradiation and p53 to mitochondrial apoptosis, the apoptosis level and gene expression were analyzed in the presence of PFT-α, a chemical compound that selectively blocks the potential transactivation of p53 and p53 downstream genes in a variety of cell types [69], [70]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bivalves play vital roles in marine, brackish, freshwater and terrestrial habitats. In recent years, these ecosystems have become affected through anthropogenic activities. The ecological success of marine bivalves is based on the ability to modify their physiological functions in response to environmental changes. One of the most important mechanisms involved in adaptive responses to environmental and biological stresses is apoptosis, which has been scarcely studied in mollusks, although the final consequence of this process, DNA fragmentation, has been frequently used for pollution monitoring. Environmental stressors induce apoptosis in molluscan cells via an intrinsic pathway. Many of the proteins involved in vertebrate apoptosis have been recognized in model invertebrates; however, this process might not be universally conserved. Mytilus galloprovincialis is presented here as a new model to study the linkage between molecular mechanisms that mediate apoptosis and marine bivalve ecological adaptations. Therefore, it is strictly necessary to identify the key elements involved in bivalve apoptosis. In the present study, six mitochondrial apoptotic-related genes were characterized, and their gene expression profiles following UV irradiation were evaluated. This is the first step for the development of potential biomarkers to assess the biological responses of marine organisms to stress. The results confirmed that apoptosis and, more specifically, the expression of the genes involved in this process can be used to assess the biological responses of marine organisms to stress.
    PLoS ONE 04/2013; 8(4):e61502. DOI:10.1371/journal.pone.0061502 · 3.23 Impact Factor
  • Source
    • "However, this response is much less desirable when the hypoxia is due to ischemia following stroke or myocardial infarction. Indeed, inhibition of p53 seems to be extremely beneficial during the early stages of ischemia or during subsequent reperfusion injury (Liu et al., 2006). The activation of p53 by ribosomal stress has been linked to tumor suppression , with abnormalities in the expression of several ribosomal proteins resulting in an increased tumor susceptibility in disorders such as Diamond Blackfan Anemia, possibly reflecting a failure to properly activate p53 (Montanaro et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: While the tumor suppressor functions of p53 have long been recognized, the contribution of p53 to numerous other aspects of disease and normal life is only now being appreciated. This burgeoning range of responses to p53 is reflected by an increasing variety of mechanisms through which p53 can function, although the ability to activate transcription remains key to p53's modus operandi. Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision we must understand if we are to exploit efficiently the next generation of drugs that selectively activate or inhibit p53.
    Cell 06/2009; 137(3):413-31. DOI:10.1016/j.cell.2009.04.037 · 32.24 Impact Factor
Show more