Pifithrin-alpha attenuates p53-mediated apoptosis and improves cardiac function in response to myocardial ischemia/reperfusion in aged rats.
ABSTRACT 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.
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ABSTRACT: A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cytoplasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion (I/R) injury. This tightly orchestrated catabolic cellular 'housekeeping' process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protective mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the variability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin (mTOR) inhibitors, adenosine monophosphate-activated protein kinase (AMPK) modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic manipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.
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ABSTRACT: Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell-cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myocardial growth and angiogenesis in the pathophysiology of cardiac hypertrophy and heart failure.Circulation Research 01/2014; 114(3):565-571. DOI:10.1161/CIRCRESAHA.114.300507 · 11.09 Impact Factor
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ABSTRACT: The p53 protein family, comprising p53, p63 and p73, is primarily involved in preserving genome integrity and preventing tumor onset, and also affects a range of physiological processes. Signal-dependent modifications of its members and of other pathway components provide cells with a sophisticated code to transduce a variety of stress signaling into appropriate responses. TP53 mutations are highly frequent in cancer and lead to the expression of mutant p53 proteins that are endowed with oncogenic activities and sensitive to stress signaling. p53 family proteins have unique structural and functional plasticity, and here we discuss the relevance of prolyl-isomerization to actively shape these features. The anti-proliferative functions of the p53 family are carefully activated upon severe stress and this involves the interaction with prolyl-isomerases. In particular, stress-induced stabilization of p53, activation of its transcriptional control over arrest- and cell death-related target genes and of its mitochondrial apoptotic function, as well as certain p63 and p73 functions, all require phosphorylation of specific S/T-P motifs and their subsequent isomerization by the prolyl-isomerase Pin1. While these functions of p53 counteract tumorigenesis, under some circumstances their activation by prolyl-isomerases may have negative repercussions (e.g. tissue damage induced by anticancer therapies and ischemia-reperfusion, neurodegeneration). Moreover, elevated Pin1 levels in tumor cells may transduce deregulated phosphorylation signaling into activation of mutant p53 oncogenic functions. The complex repertoire of biological outcomes induced by p53 finds mechanistic explanations, at least in part, in the association between PPIases and the p53 pathway. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. Copyright © 2015. Published by Elsevier B.V.