Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53

Zhang, Chi; Feng, Yan; Qu, Shunlin; Wei, Xing; Zhu, Honglin; Luo, Qi; Liu, Meidong; Chen, Guangwen; Xiao, Xianzhong

doi:10.1093/cvr/cvr022

Cited by 175 publications

(134 citation statements)

References 27 publications

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“…SIRT1 activator resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis and reduces p53 acetylation [42]. Here we found that acetylation of endogenous p53 was significantly increased with SIRT1H363Y overexpression, and Bax expression was abundant and dramatically upregulated at both the RNA and protein levels in the dilated TG mouse hearts ( Figure 6A, B and D).…”

Section: Discussionmentioning

confidence: 58%

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Zhang

Tang

et al. 2014

Sci. China Life Sci.

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SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), is an NAD + -dependent protein deacetylase that plays a critical role in the regulation of vascular function. The current study aims to investigate the functional significance of deacetylase activity of SIRT1 in heart. Here we show that the early postnatal hearts expressed the highest level of SIRT1 deacetylase activity compared to adult and aged hearts. We generated transgenic mice with cardiac-specific expression of a dominant-negative form of the human SIRT1 (SIRT1H363Y), which represses endogenous SIRT1 activity. The transgenic mice displayed dilated atrial and ventricular chambers, and died early in the postnatal period. Pathological, echocardiographic and molecular phenotype confirmed the presence of dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed a greater abundance of apoptotic nuclei in the hearts of transgenic mice. Furthermore, we show that cardiomyocyte apoptosis caused by suppression of SIRT1 activity is, at least in part, due to increased p53 acetylation and upregulated Bax expression. These results indicate that dominant negative form of SIRT1 (SIRT1H363Y) overexpression in mouse hearts causes cardiomyocyte apoptosis and early-onset heart failure, suggesting a critical role of SIRT1 in preserving normal cardiac development during the early postnatal period. deacetylase, SIRT1, apoptosis, heart failure Citation:

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Section: Discussionmentioning

confidence: 58%

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Zhang

Tang

et al. 2014

Sci. China Life Sci.

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“…Previous studies showed that resveratrol has acute antioxidant and antiinflammatory effects (Hung et al, 2000;Alcendor et al, 2007;Ghanim et al, 2011), and could also inhibit doxorubicin-induced cardiomyocyte apoptosis (Zhang et al, 2011a). Reduction of myocardial oxidative stress and apoptosis can improve cardiac function in heart failure (Lu et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Through Langendorff perfusing, we found that SIRT1(+/-) mice had lower heart function compared with WT mice. SIRT1, an essential endogenous apoptosis inhibitor in cardiac myocytes (Alcendor et al, 2004;Zhang et al, 2011a), plays an important role in heart development. SIRT1-defective mice have shown congenital heart disease (Cheng et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol, an activator of SIRT1, upregulates AMPK and improves cardiac function in heart failure

Gu¹,

Wang²,

Ye³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Reduced AMP-activated protein kinase (AMPK) expression has been shown to play a significant role in the cardiac dysfunction in heart failure. This study was designed to examine the effect of resveratrol, a potent activator of silent information regulator (SIRT1), on cardiac function and AMPK expression in heart failure. Adult male rat left anterior descending arteries were ligated, and they were fed with either a regular diet or a diet enriched with resveratrol. Heart failure was produced by myocardial infarction, and was associated with markedly increased AMPK and SIRT1 protein levels. Resveratrol treatment had a tremendous beneficial effect, both in terms of improving AMPK expression and on cardiac function. Decreased cardiac function and AMPK expression were also found in SIRT1 knockout (+/-) mice. In cultured cardiomyocytes, resveratrol increased AMPK and SIRT1 expressions, and overexpression of SIRT1 was found to be sufficient to activate AMPK in H9c2 cells. In contrast, pretreatment of cardiomyocytes with an SIRT1 antagonist, nicotinamide, blocked these beneficial effects of resveratrol. Therefore, the protective effects of resveratrol were found to be dependent on its ability to activate SIRT1 and improve AMPK expression. These results demonstrated that in heart failure, the enzymatic activity of cardiac SIRT1 is increased, which contributes to increased expression of AMPK, and resveratrol enhances the expression of AMPK and improves cardiac function through the activation of SIRT1.

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“…Annexin A5 (AnxA5) is a human protein (35 kDa) that has been extensively used to detect phosphatidylserine-exposing cells (8), for example, for detection of apoptosis and cell death, which is altered in numerous diseases and treatments. Phosphatidylserines switch from the inner to the outer leaflet of the cell membrane within a few hours after initiating stimuli of apoptosis and other cell conditions and represent a highly accessible target for AnxA5 with a strong binding affinity (9).…”

mentioning

confidence: 99%

XTEN-Annexin A5: XTEN Allows Complete Expression of Long-Circulating Protein-Based Imaging Probes as Recombinant Alternative to PEGylation

et al. 2014

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The coupling of polyethylene glycol (PEG) to proteins (PEGylation) has become a standard method to prolong blood circulation of imaging probes and other proteins, liposomes, and nanoparticles. However, concerns have arisen about the safety of PEG, especially with respect to its poor biodegradability and antibody formation, including new evidence about preformed anti-PEG antibodies in a quarter of healthy blood donors. Here, we apply a new hydrophilic polypeptide XTEN to extend the blood half-life of an imaging probe. As an example, we chose annexin A5 (AnxA5), a recombinant 35-kD protein extensively used for the in vitro and in vivo detection of apoptosis, that has a blood half-life of less than 7 min in mice, limiting its accumulation in target tissues and therefore limiting its utility as an imaging reagent. Methods: The sequence of XTEN was developed by Volker Schellenberger and colleagues by evolutionary in vitro optimization to yield PEG-like properties but provides several key advantages in comparison to PEG. The DNA of a 288-amino-acid version of XTEN with an additional Nterminal cysteine for site-directed coupling was fused to AnxA5 (XTENAnxA5). The fusion protein could be highly expressed in Escherichia coli and efficiently purified using XTEN conveniently as a purification tag. It was labeled with a thiol-reactive fluorescent dye and via a chelator with a radionuclide. Results: SPECT/CT imaging revealed a blood half-life of about 1 h in mice, markedly longer than the 7-min blood half-life for unmodified AnxA5, which should allow improved imaging of target tissues with low perfusion. In comparison to AnxA5, XTENAnxA5 demonstrated a substantially higher accumulation in tumors under chemotherapy in near-infrared fluorescence imaging. Conclusion: The presented method allows the expression and production of high amounts of long-circulating XTEN-AnxA5 without the necessity of PEGylation, thereby simplifying the synthesis while avoiding labelinginduced inactivation of AnxA5 and potential adverse effects of PEG. It is readily applicable to other recombinant protein or peptide-based imaging probes and allows fine-tuning of the desired blood half-life, because longer XTEN variants yield longer blood half-lives.

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Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53

Abstract: The protective effect of RES against DOX-induced cardiomyocyte apoptosis is associated with the up-regulation of SIRT1-mediated p53 deacetylation.

Cited by 175 publications

References 27 publications

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Resveratrol, an activator of SIRT1, upregulates AMPK and improves cardiac function in heart failure

XTEN-Annexin A5: XTEN Allows Complete Expression of Long-Circulating Protein-Based Imaging Probes as Recombinant Alternative to PEGylation

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