Endothelial Smad3 as a Novel Target to Avert Chemotherapy Induced Cardiomyopathy

项目摘要/摘要 由于早期发现、改进的治疗方法和支持性护理方面的进步，癌症存活率 在过去的几十年里大大增加了。这一成功转化为癌症数量的迅速增加 患有心血管并发症的幸存者接受抗癌治疗。特别值得关注的是 阿霉素和其他用于治疗血液系统恶性肿瘤、乳腺、卵巢、 和其他实体瘤。接受这些药物治疗的患者会遭受长期的心脏损伤和重构。 被称为阿霉素心肌病。大多数研究都将心肌细胞作为其直接靶点。 阿霉素。我们最近发现，微血管内皮细胞是阿霉素治疗血管内皮细胞损伤的关键靶点。 心。具体地说，我们检测到内皮基因表达的变化模式和不利的心脏 阿霉素治疗完成后持续的重塑，并由典型的转化生长因子-2介导 β途径。虽然我们已经确定了转化生长因子-β/Smad3通路参与了内皮损伤 通过阿霉素，下游过程仍然未知。此外，大多数实验研究都是关于 阿霉素心脏毒性已在雄性动物身上进行，并在患病率和性别上存在差异 心肌病的机制还没有得到充分的解决。我们建议检验一个假设 阿霉素通过上调转化生长因子-β/Smad3途径促进内皮重编程，以及 抑制内皮细胞中Smad3转录活性将缓解内皮细胞重新编程和 阿霉素治疗动物的心肌病。具体目标1旨在评估转化生长因子-1的作用 β/Smad3通路在阿霉素诱导的男女血管内皮细胞向间充质细胞重编程中的作用 血管内皮细胞。我们计划利用SMAD3缺陷的人内皮细胞系和转基因小鼠品系来 检测这一通路在激活间充质/纤维化程序和抑制血管生成中的作用。 阿霉素诱导的血管内皮细胞特异性转录。在具体目标2中，我们建议审查 内皮细胞Smad3促进阿霉素治疗后不良心血管重构和功能障碍 雌性和雄性小鼠。虽然我们之前的研究使用的是全球Smad3基因敲除模型，但现在我们已经 产生了一种新的转基因菌株，具有内皮Smad3基因敲除，将使我们能够直接 阐述心脏内皮细胞在阿霉素心肌病中的作用。我们建议在临床上使用一种 在雌性和雄性小鼠中建立阿霉素心肌病的相关模型，将使我们能够评估 内皮细胞Smad3在持续性内皮功能障碍、微血管重构和心脏受压中的作用 功能。KCU骨科医学院和生物科学学院的学生将参与 提出研究课题。我们预计，拟议的方法将有助于开发新的血管系统。 靶向治疗以保持内皮弹性和防止心脏重塑和进展 心肌病。

PROJECT SUMMARY / ABSTRACT Due to advances in early detection, improved therapies and supportive care, cancer survival rates have increased substantially over the past decades. This success translates into a rapidly increasing number of cancer survivors who suffer from cardiovascular complications of anticancer therapy. Of particular concern are doxorubicin and other anthracycline drugs that are used to treat hematological malignancies, breast, ovarian, and other solid tumors. Patients treated with these drugs suffer from long-term cardiac damage and remodeling known as doxorubicin cardiomyopathy. Most studies have focused on cardiomyocytes as a direct target of doxorubicin. We have recently shown that microvascular endothelium is a critical target of doxorubicin in the heart. Specifically, we detected an altered pattern of endothelial gene expression and adverse cardiac remodeling that persisted after completion of the doxorubicin treatment and was mediated by the canonical TGF- beta pathway. While we have established involvement of the TGF-beta/Smad3 pathway in endothelial damage by doxorubicin, the downstream processes remain unknown. Additionally, most of experimental studies on doxorubicin cardiotoxicity have been performed on male animals and sex-specific differences in prevalence and mechanisms of cardiomyopathy have not been adequately addressed. We propose to test a hypothesis that doxorubicin promotes endothelial reprogramming via upregulation of the TGF-beta/Smad3 pathway, and suppression of Smad3 transcriptional activity in endothelial cells will alleviate endothelial reprogramming and cardiomyopathy in doxorubicin treated animals. Specific Aim 1 is designed to assess the role of the TGF- beta/Smad3 pathway in endothelial-to-mesenchymal reprogramming by doxorubicin in female and male endothelia. We plan to utilize Smad3 deficient human endothelial cell lines and transgenic mouse strains to examine the role of this pathway in both activation of the mesenchymal/profibrotic program and suppression of endothelium specific transcription by doxorubicin. In Specific Aim 2, we propose to examine the role of endothelial Smad3 in promoting adverse cardiovascular remodeling and dysfunction in doxorubicin treated female and male mice. While our prior studies utilized a model of global Smad3 knockout, we have now generated a novel transgenic strain featuring an endothelial Smad3 knockout that will enable us to directly address the role of cardiac endothelial cells in doxorubicin cardiomyopathy. We propose to utilize a clinically relevant model of doxorubicin cardiomyopathy in female and male mice that will allow us to evaluate the role of endothelial Smad3 in sustained endothelial dysfunction, microvascular remodeling, and depressed cardiac function. Students at the Colleges of Osteopathic Medicine and Biosciences at KCU will be involved in the proposed research project. We anticipate that the proposed approach will help develop novel vasculature targeted therapies to preserve endothelial resiliency and prevent cardiac remodeling and progression of cardiomyopathy.