Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice

Abstract

Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6-8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31 +/- 16% (P < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress.

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

“…Promotion of p53 activity, already shown in other biological contexts, is prompted by nucleolar stress in an early cellular response preceding p53 activation and the induction of a suicide signal program (1,3,4,26,27). Although the importance of multiple pathways to explain DOX-mediated pathogenesis should not be underestimated, data presented herein implicate nucleolar stress as an important mechanism of DOX cardiotoxicity and corroborate reports that DOX cardiotoxic effects are ameliorated by p53 inhibition (37)(38)(39).…”

The involvement of Nox4 in fine particulate matter exposure-induced cardiac injury in mice

“…It had been suggested that up-regulated Bax protein and down-regu-lated Bcl-2 protein activated the apoptotic pathway (Zhu et al, 2015;Gupta and Knowlton, 2005). In the cardiovascular system, p53 or Bax-mediated signaling pathway in the apoptosis of cardiomyocytes was recently shown to have a crucial function in the development of HF (Shizukuda et al, 2005;Qin et al, 2006). In our study, we found that PM 2.5 exposure up-regulates p53, Bax and Caspase-1 protein in cardiac tissues and decreases the expression of Bcl-2, while the ratio of Bcl-2/Bax is also increased.…”

Angiotensin II Receptor Antagonist Attenuates Expression of Aging Markers in Diabetic Mouse Heart

“…38 p53 knockout mice are associated with reduced doxorubicin-induced myocardial dysfunction. 39 Thus, the increase of senescence-associated molecules may be involved in the cardiac dysfunction of db/db mice, and candesartan may improve cardiac function, in part, by reducing the amount of these senescenceassociated molecules.…”