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Angiotensin II-induced p53-dependent cardiac apoptotic cell death: its prevention by metallothionein.
Toxicol Lett. 2009 Dec 15; 191(2-3):314-20.TL

Abstract

Apoptotic cell death was found to play a critical role in the development of diabetic cardiomyopathy. As one of pathogenic components of diabetes angiotensin II (Ang II) induced cardiac cell death in vitro and in vivo through induction of reactive oxygen and nitrogen species. However, Ang II-induced cell death signaling in the heart remains unclear. The present study was to investigate whether Ang II induces p53 expression and activation and if so, whether Ang II-induced cardiac cell death is p53-dependent, and whether a potent antioxidant metallothionein (MT) prevents Ang II-induced p53 expression, and associate apoptotic cell death signaling. A cardiac cell line (H9c2) was exposed to Ang II. We found that exposure of H9c2 cells to Ang II at 10, 50 and 100 nM for 24 h induced a significant apoptotic effect, measured by DNA fragmentation and cleaved caspase-3. Induction of apoptotic cell death by Ang II can be completely blocked by p53 inhibitor Pitithrin-alpha. Exposure of H9c2 cells to Ang II also significantly increased p53 phosphorylation, DNA double strand breaks and Bax/Bcl-2 ratio. All these effects were not observed in H9c2MT7 cells that forcedly overexpresses human MT-IIA gene, suggesting the preventive effect of antioxidant MT against Ang II-induced p53 activation and its apoptotic death signaling. Furthermore, the in vitro finding was validated in animal models by supplying Ang II to wild-type mice (WT) and MT-TG mice that has cardiac-specifically overexpressed MT gene. Ang II-induced significant up-regulation of p53 expression along with an increase in Bax/Bcl-2 ratio in the hearts of WT mice, but not MT-TG mice. These results suggest that Ang II-induced cardiac apoptotic cell death is mediated by p53 apoptotic signaling pathway, which is related to oxidative stress. Antioxidant MT can completely prevent Ang II-induced p53 activation and associated apoptotic effect in the heart.

Authors+Show Affiliations

Department of Hematology & Oncology at the First Hospital of Jilin University, Changchun, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19808082

Citation

Liu, Qiuju, et al. "Angiotensin II-induced P53-dependent Cardiac Apoptotic Cell Death: Its Prevention By Metallothionein." Toxicology Letters, vol. 191, no. 2-3, 2009, pp. 314-20.
Liu Q, Wang G, Zhou G, et al. Angiotensin II-induced p53-dependent cardiac apoptotic cell death: its prevention by metallothionein. Toxicol Lett. 2009;191(2-3):314-20.
Liu, Q., Wang, G., Zhou, G., Tan, Y., Wang, X., Wei, W., Liu, L., Xue, W., Feng, W., & Cai, L. (2009). Angiotensin II-induced p53-dependent cardiac apoptotic cell death: its prevention by metallothionein. Toxicology Letters, 191(2-3), 314-20. https://doi.org/10.1016/j.toxlet.2009.09.015
Liu Q, et al. Angiotensin II-induced P53-dependent Cardiac Apoptotic Cell Death: Its Prevention By Metallothionein. Toxicol Lett. 2009 Dec 15;191(2-3):314-20. PubMed PMID: 19808082.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin II-induced p53-dependent cardiac apoptotic cell death: its prevention by metallothionein. AU - Liu,Qiuju, AU - Wang,Guanjun, AU - Zhou,Guihua, AU - Tan,Yi, AU - Wang,Xiuli, AU - Wei,Wei, AU - Liu,Lucheng, AU - Xue,Wanli, AU - Feng,Wenke, AU - Cai,Lu, Y1 - 2009/10/04/ PY - 2009/08/23/received PY - 2009/09/25/revised PY - 2009/09/28/accepted PY - 2009/10/8/entrez PY - 2009/10/8/pubmed PY - 2009/12/16/medline SP - 314 EP - 20 JF - Toxicology letters JO - Toxicol Lett VL - 191 IS - 2-3 N2 - Apoptotic cell death was found to play a critical role in the development of diabetic cardiomyopathy. As one of pathogenic components of diabetes angiotensin II (Ang II) induced cardiac cell death in vitro and in vivo through induction of reactive oxygen and nitrogen species. However, Ang II-induced cell death signaling in the heart remains unclear. The present study was to investigate whether Ang II induces p53 expression and activation and if so, whether Ang II-induced cardiac cell death is p53-dependent, and whether a potent antioxidant metallothionein (MT) prevents Ang II-induced p53 expression, and associate apoptotic cell death signaling. A cardiac cell line (H9c2) was exposed to Ang II. We found that exposure of H9c2 cells to Ang II at 10, 50 and 100 nM for 24 h induced a significant apoptotic effect, measured by DNA fragmentation and cleaved caspase-3. Induction of apoptotic cell death by Ang II can be completely blocked by p53 inhibitor Pitithrin-alpha. Exposure of H9c2 cells to Ang II also significantly increased p53 phosphorylation, DNA double strand breaks and Bax/Bcl-2 ratio. All these effects were not observed in H9c2MT7 cells that forcedly overexpresses human MT-IIA gene, suggesting the preventive effect of antioxidant MT against Ang II-induced p53 activation and its apoptotic death signaling. Furthermore, the in vitro finding was validated in animal models by supplying Ang II to wild-type mice (WT) and MT-TG mice that has cardiac-specifically overexpressed MT gene. Ang II-induced significant up-regulation of p53 expression along with an increase in Bax/Bcl-2 ratio in the hearts of WT mice, but not MT-TG mice. These results suggest that Ang II-induced cardiac apoptotic cell death is mediated by p53 apoptotic signaling pathway, which is related to oxidative stress. Antioxidant MT can completely prevent Ang II-induced p53 activation and associated apoptotic effect in the heart. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/19808082/Angiotensin_II_induced_p53_dependent_cardiac_apoptotic_cell_death:_its_prevention_by_metallothionein_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(09)01439-8 DB - PRIME DP - Unbound Medicine ER -