Role of oxidative stress in doxorubicin-induced cardiotoxicity racial disparities

氧化应激在阿霉素引起的心脏毒性种族差异中的作用

• 批准号: 10994869
• 负责人: Tarek Magdy Mohamed
• 金额: $ 21.9万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10994869
• 关键词: Role; oxidative; stress; doxorubicin; induced

African Americans show a 3-fold higher risk of doxorubicin-cardiotoxicity than their White counterparts. Oxidative stress is a major underlying mechanism of dox-cardiotoxicity and is significantly aggravated in African American compared to their white counterparts suggesting a role in dox­ cardiotoxicity racial disparities. Our preliminary data identified EPHA2.AS1 as a novel gene that might regulate dox-cardiotoxicity. Importantly, race-specific SNPs in EPHA2-AS1 are associated with altered EPHA2 expression, calcium levels, and hepatic inflammatory markers. EPHA2.AS1 is located on the antisense strand adjacent to EPH receptor A2 (EPHA2). EPHA2 promotes mitochondrial dysregulation and oxidative stress and is upregulated during the pathogenesis of multiple diseases. Therefore, we hvaothesize that heart cells generated from African Americans are more p_rone to severe dox-induced cardiotoxicity than White Americans due to altered oxidative stress cardiac regulation and that EPHA2.AS1 regulates EPHA2 in the human heart, which dvsregulates cardiac mitochondria, exacerbating dox-induced cardiotoxicity. We will use a cohort of patient-specific human induced pluripotent stem cell-cardiomyocytes derived from African and White Americans with and without dox-cardiotoxicity to examine ROS production, investigate their effect on dox-cardiotoxicity using our well-established biochemical and functional assays, reveal genes/pathways implicating their race-specific cardiac regulation using RNA-Seq, and screen for cardioprotective antioxidants in iPSC-cardiomyocytes and mice (Aim1). In Alm 2, we will define the role of EPHA2.AS1 in mitochondrial dysregulation-driven dox-cardiotoxicity racial disparities. We will use CRISPR-Cas9-generated EPHA2.AS1 KO, OE, and isogenic iPSC-cardiomyocytes to assess its effect on the severity of dox-cardiotoxicity and on EPHA2 regulation and signaling. Furthermore, we will use CRIPSR-Cas9 to introduce potential candidate EPHA2.AS1 race-specific SNPs in isogenic iPSC-cardiomyocytes followed by characterization of mitochondria dysregulation-driven dox-cardiotoxicity. Moreover, we will use an Epha2 KO mouse to assess the implication of Epha2 in dox-cardiotoxicity in vivo.

非裔美国人患阿霉素心脏毒性的风险比白人高3倍。氧化应激是dox-心脏毒性的主要潜在机制，与白人相比，非裔美国人的氧化应激显著加重，这表明氧化应激在dox-心脏毒性的种族差异中起作用。我们的初步数据鉴定了EPHA2。AS1作为一个可能调控犬心脏毒性的新基因。重要的是，EPHA2- as1的种族特异性snp与EPHA2表达、钙水平和肝脏炎症标志物的改变有关。EPHA2。AS1位于EPH受体A2 （EPHA2）附近的反义链上。EPHA2促进线粒体失调和