alexa Neuregulin1 Improved Cardiac Function in Doxorubicin-Tr
ISSN: 2329-9517

Journal of Cardiovascular Diseases & Diagnosis
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Research Article

Neuregulin1 Improved Cardiac Function in Doxorubicin-Treated Mice with Cardiomyocyte-Specific over expression of a Dominant-Negative PI3Kp110α

Yun Bian1, Marcy Silver1, Jillian Onufrak1, Kalon K.L. Ho2, Mark A. Marchionni3, Peter M Kang2, David A Goukassian1, Joseph Carrozza1, James P Morgan1 and Xinhua Yan1*

1Cardiovascular Research, Department of Medicine, Steward St. Elizabeth’s Medical Center and Tufts University School of Medicine, Boston, USA

2Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA

3Alzcor Pharmaceuticals Inc. Arlington, USA

Corresponding Author:
Xinhua Yan
Cardiovascular Research, St. Elizabeth’s Medical Center
736 Cambridge St. CBR345, Boston, MA 02135
Tel: 001-617-562-7608
E-mail: [email protected]

Received July 30, 2013; Accepted August 22, 2013; Published August 29, 2013

Citation: Bian Y, Silver M, Onufrak J, Ho KKL, Marchionni MA, et al. (2013) Neuregulin1 Improved Cardiac Function in Doxorubicin-Treated Mice with Cardiomyocyte-Specific over expression of a Dominant-Negative PI3Kp110α. J Cardiovasc Dis Diagn 1:120. doi: 10.4172/2329-9517.1000120

Copyright: © 2013 Bian Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

Abstract

Neuregulin1s (NRG1s) are effective for protecting the heart from various stresses. Our previous studies show that heterozygous knockout of the NRG1 gene worsens while injections of a recombinant NRG1 improve cardiac function in Chemotherapy Drug Doxorubicin (DOX) - treated mice. In cultured cardiomyocytes, studies show that the Phosphoinositide 3-Kinase (PI3K) pathway is necessary for NRG1 to reduce DOX-induced apoptosis and loss of cardiac troponins. Here, we test whether PI3Kp110α, a Class IA PI3K isoform, is necessary for NRG1’s cardioprotective effects in DOX-treated mice. DOX was administered to mice with cardiomyocyte-specific overexpression of a constitutively active PI3Kp110α (CaPI3K), or a dominant negative PI3Kp110α (dnPI3K). Solvent or NRG1 was administered concurrently with DOX to dnPI3K mice. Our results showed that survival and cardiac function were improved in CaPI3K, but worsened in dnPI3K mice. Concurrent NRG1 injections significantly improved survival and cardiac function in dnPI3K mice, which were associated with increased activation of ERK1/2 and mTORC1 in the heart. These results have demonstrated that PI3Kp110α is important for protecting the heart from DOX. Further, the results suggest that PI3Kp110α is not necessary for NRG1 to protect the heart from DOX. NRG1 may protect the heart by activating alternative survival pathways, such as ERK1/2 and mTORC1, in DOX-treated dnPI3K mouse hearts.

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