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Cardioprotective Effect of Survivin in Doxorubicin-Induced Myocardial Injury Model

Authors
 이범섭 
Issue Date
2015
Description
의과대학/박사
Abstract
Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, belongs to the inhibitor of apoptosis protein (IAP) family is associated with apoptosis and alteration of cardiomyocyte molecular pathways. Recent studies have shown that reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the mechanism by which survivin mediates the cardioprotective effect against doxorubicin-associated injury has not been fully determined. Therefore, we investigated the anti-apoptotic effect and molecular cellular mechanisms of survivin using a protein delivery system in doxorubicin-induced cardiomyocyte injury model.

We demonstrated that treatment of doxorubicin resulted in a significant decrease of survivin expression in the H9c2 cardiomyocyte cell line and Sprague Dawley rat hearts. In addition, Sp1 play a role in the upregulation of survivin expression, doxorubicin treatment increases a degradation of Sp1 protein via proteasome-mediated proteolysis. Transcription of survivin decreases by activation of p53. The effect of doxorubicin is consistent with the observed increase p53 protein level and the phosphorylation level at Ser15 in the cardiomyocyte. Following doxorubicin treatment of the cardiomyocyte, the survivin promoter has reduced levels of bound Sp1, but an increased level of bound p53. Moreover, the upstream signaling Sp1 protein, such as Akt, mTOR and p70s6k, were also decreased by doxorubicin treatment.

We constructed a recombinant survivin fused to the protein transduction domain (PTD) derived from HIV-TAT protein. And, Purified recombinant TAT-survivin protein were efficiently delivered to H9c2 cardiomyocyte cell line and Sprague Dawley rat hearts via intraperitoneal injection, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity, and apoptotic index concomitantly with increased cell viability against doxorubicin-associated injury. Moreover, TAT-Survivin protein-pretreated hearts demonstrated decreased less cardiomyocyte vacuolation and myofibrillar disarray, compared with doxorubicin-associated injury hearts.

We evaluated the effect of TAT-survivin protein on cardiac functional recovery using Langendorff system. After ischemia-reperfusion injury, cardioprotective effect of TAT-survivin such as functional recovery measured by LVDP (left ventricular developed pressure) and RPP (rate pressure product) was observed.

Furthermore, the survivin pretreatment using PTD-mediated delivery has a potential cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis through the mechanism involving a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl2 and activated nuclear translocation of CREB.

Present study suggest that firstly, survivin may be an important protein in the process of doxorubicin-induced cardiomyocyte injury, and secondly, TAT-survivin protein has a potentially protective effect against doxorubicin-induced cardiomyocyte apoptosis. Taken together, these results may provide the insight for future development of drugs targeted on myocardial protection under cardiovascular diseases.
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Appears in Collections:
1. College of Medicine (의과대학) > Others (기타) > 3. Dissertation
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/148714
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