Radiation injury to the heart

本申请的目的是了解全身照射（TBI）引起的冠状动脉硬化和心功能障碍的机制，并确定和制定减轻和/或治疗此类损伤的医疗对策。我们的初步研究表明，10戈伊单次剂量TBI，剂量和时间表相关的放射性恐怖袭击和核事故，与心血管疾病，冠状动脉硬化和心脏功能损伤的危险因素的发展。此外，药物氯沙坦和营养药物姜黄素似乎可以预防TBI诱导的心血管疾病风险因素的发展。虽然有大量的文献关于TBI在器官如肠和肾中的影响，但没有关于TBI导致心脏损伤的机制的信息。导致TBI后冠状动脉硬化和心室功能障碍的分子和细胞事件的顺序尚不清楚。我们假设TBI引起的心脏损伤是心血管疾病危险因素增加的结果。这一假设的推论是，降低心血管疾病危险因素的药物治疗将有效治疗TBI诱导的冠状动脉硬化和心室功能障碍。将在已建立的大鼠骨髓移植模型中检验该假设。将测试三个特定目标：特定目标1将确定TBI导致血管系统促凝血和抗凝功能失衡的程度，从而导致冠状动脉硬化和心室功能障碍。具体目标2将确定TBI间接损伤冠状血管/内皮以减少一氧化氮并增加一氧化氮合酶产生超氧化物的机制。具体目标3将确定医疗对策在辐射暴露后减轻或治疗TBI引起的心血管系统损伤的能力。这些研究将确定TBI诱导的冠状血管和心室功能损伤的潜在机制，并确定现有药物对策减轻和/或治疗辐射诱导的心血管系统损伤的能力。 1

The objective of this application is to understand the mechanisms responsible for coronary sclerosis and cardiac dysfunction induced by total body irradiation (TBI), and to identify and develop medical countermeasures to mitigate and/or treat such injury. Our preliminary studies indicate that 10 Gy single-dose TBI, a dose and schedule relevant to radiological terrorist attacks and nuclear accidents, is associated with the development of risk factors for cardiovascular disease, coronary sclerosis and functional injury to the heart. Furthermore, the pharmaceutical Losartan and the nutriceutical curcumin appear to prevent TBI-induced development of risk factors for cardiovascular disease. Whereas there is a substantial body of literature regarding the impact of TBI in organs such as the intestine and kidney, there is no information about the mechanisms by which TBI causes injury to the heart. The sequence of the molecular and cellular events that result in coronary sclerosis and ventricular dysfunction following TBI is not known. We hypothesize that TBI-induced damage to the heart results from increased risk factors for cardiovascular disease. The corollary to this hypothesis is that pharmaceutical treatments that decrease risk factors for cardiovascular disease will be effective in treating TBI-induced coronary sclerosis and ventricular dysfunction. This hypothesis will be tested in an established rat bone marrow transplant model. Three specific aims will be tested: Specific Aim 1 will determine the extent that TBI results in an imbalance between procoagulant and anticoagulant function of the vasculature resulting in coronary sclerosis and ventricular dysfunction. Specific Aim 2 will determine the mechanisms by which TBI indirectly injures the coronary vasculature/endothelium to decrease nitric oxide and increases superoxide production from nitric oxide synthase. Specific Aim 3 will determine the ability of a medical countermeasure to mitigate or treat TBI induced injury to the cardiovascular system when given after radiation exposure. These studies will define mechanisms underlying TBIinduced injury to the coronary vasculature and ventricular function and determine the ability of existing pharmaceuticals countermeasures to mitigate and/or treat radiation-induced injury to the cardiovascular system. 1