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TRANSPLANTATION OF PLURIPOTENT STEM CELLS CONFERS CARDIAC PROTECTION IN DOX-INDUCED HEART FAILURE THROUGH NOTCH-1 PATHWAY

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Date Issued:
2012
Abstract/Description:
Doxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to reduce cardiomyocyte apoptosis in DIC; however, the effects of transplanted embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in DIC post MI are unknown. As a result, we wanted to understand how transplanted ES and iPS cells and the factors released by them inhibit apoptosis and improve cardiac function in DIC post MI. C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were treated with DOX (12 mg/kg, cumulative dose) followed by left coronary artery ligation to induce MI. ES or iPS cells (5 x 104) were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice sacrificed, and hearts harvested for further analyses. To investigate if protective effects are provided by factors released from ES and iPS cells in DIC, we performed in vitro studies using condition media (CM) obtained from ES or iPS cells to treat DOX-induced cardiotoxicity in H9c2 cells. Our data reveal that apoptosis was significantly inhibited in the ES and iPS cell transplanted hearts as well as ESCM and iPSCM treated cells compared with the untreated controls. Furthermore, a significant increase in levels of Notch-1, Hes1, and pAkt survival protein were observed. Decreased levels of PTEN, a negative regulator of Akt pathway, along with improved heart function were also observed in the stem cell transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced apoptosis in vivo, which is associated with improved cardiac function. Moreover, decreased apoptosis in both in vitro and in vivo models is mediated by the Notch pathway.
Title: TRANSPLANTATION OF PLURIPOTENT STEM CELLS CONFERS CARDIAC PROTECTION IN DOX-INDUCED HEART FAILURE THROUGH NOTCH-1 PATHWAY.
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Name(s): Merino-Chavez, Hilda, Author
Singla, Dinender, Committee Chair
Zervos, Antonis, Committee Member
Naser, Saleh, Committee Member
, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2012
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Doxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to reduce cardiomyocyte apoptosis in DIC; however, the effects of transplanted embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in DIC post MI are unknown. As a result, we wanted to understand how transplanted ES and iPS cells and the factors released by them inhibit apoptosis and improve cardiac function in DIC post MI. C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were treated with DOX (12 mg/kg, cumulative dose) followed by left coronary artery ligation to induce MI. ES or iPS cells (5 x 104) were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice sacrificed, and hearts harvested for further analyses. To investigate if protective effects are provided by factors released from ES and iPS cells in DIC, we performed in vitro studies using condition media (CM) obtained from ES or iPS cells to treat DOX-induced cardiotoxicity in H9c2 cells. Our data reveal that apoptosis was significantly inhibited in the ES and iPS cell transplanted hearts as well as ESCM and iPSCM treated cells compared with the untreated controls. Furthermore, a significant increase in levels of Notch-1, Hes1, and pAkt survival protein were observed. Decreased levels of PTEN, a negative regulator of Akt pathway, along with improved heart function were also observed in the stem cell transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced apoptosis in vivo, which is associated with improved cardiac function. Moreover, decreased apoptosis in both in vitro and in vivo models is mediated by the Notch pathway.
Identifier: CFE0004577 (IID), ucf:49213 (fedora)
Note(s): 2012-12-01
M.S.
Medicine, Molecular Biology and Microbiology
Masters
This record was generated from author submitted information.
Subject(s): Doxorubicin -- cardiomyopathy -- myocardial infarction -- apoptosis -- Notch-1
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0004577
Restrictions on Access: campus 2015-12-15
Host Institution: UCF

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