PTENuating Restenosis: An Innovative PTEN Promoter for Cardioprotection

描述（由申请人提供）：心血管疾病是导致死亡的主要原因，也是全球残疾的主要原因之一。动脉粥样硬化是心血管疾病的主要原因。可归因于心血管疾病的死亡中约有一半是由急性心脏事件引起的，包括心肌梗死。患者通常通过经皮冠状动脉介入手术进行治疗，包括血管成形术和支架置入术。不幸的是，血管的再闭塞（再狭窄）是这种手术的主要限制。PTEN（phosphatase and tensin homolog deleted from chromosome 10）被认为是抑制血管成形术后血管平滑肌细胞（vascular smooth muscle cell，SMC）增殖和迁移的潜在靶点，而SMC增殖和迁移导致病理性血管重构和再狭窄。我们最近已经鉴定了一类新的化合物，其通过上调PTEN水平选择性地抑制高度增殖细胞。因此，我们假设这些新化合物可能有效地减少再狭窄。此外，氧化应激被认为是经皮冠状动脉介入术后新生内膜增生的一个因素。我们提出了一个额外的假设，即这些化合物可以进一步修饰以包含前硝酰基官能团，这可以减少施加在受损血管组织以及下游心脏组织上的氧化应激，从而保护整个心血管系统在血运重建过程中。有限的初步实验已经显示出非常有希望的结果，这表明开发这种创新方法同时治疗再狭窄和缺血/再灌注损伤的“风险最小，回报高”。公共卫生相关性：心血管疾病是导致死亡的主要原因，也是全球残疾的主要原因之一。动脉粥样硬化是这种疾病的主要原因。患有这种疾病的患者通常使用血管成形术和支架置入术进行治疗。不幸的是，由于血管平滑肌细胞增殖和迁移，再狭窄仍然是这些手术的长期并发症。我们最近发现了一种新型化合物，它通过一种机制抑制高度增殖细胞的生长，该机制已被提议作为预防血管重塑和再狭窄的靶点。因此，我们打算在猪的心血管疾病模型中使用新化合物来测试这一想法。此外，约一半的心血管疾病死亡是由于急性心脏事件，包括心脏病发作。这种新化合物包含一个前硝酰基官能团，也可用于为心脏提供抗氧化保护，防止心脏病发作后再灌注期间的额外损伤。我们建议研究这种多模式方法的发展，以预防使人衰弱的血运重建后心血管事件。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death, and one of the primary causes of disability worldwide. Atherosclerosis is the primary contributor to cardiovascular disease. About one-half of the deaths that can be attributed to cardiovascular disease arise from acute cardiac events, including myocardial infarction. Patients are often treated through percutaneous coronary intervention procedures, including angioplasty and stent placement. Unfortunately, reocclusion of the vessel (restenosis) is a major limitation of such procedures. PTEN (phosphatase and tensin homolog deleted from chromosome 10) has been proposed as a potential target to inhibit post-angioplasty vascular smooth muscle cell (SMC) proliferation and migration, which leads to pathological vascular remodeling and restenosis. We have recently identified a novel class of compounds that selectively inhibit highly proliferative cells through upregulation of PTEN levels. We, therefore, hypothesize that these novel compounds may be effective in attenuating restenosis. In addition, oxidative stress has been implicated as a contributor to neointimal hyperplasia following percutaneous coronary intervention procedures. We propose an additional hypothesis that these compounds can be further modified to include a pro-nitroxyl functional group, which may reduce the oxidative stress imposed upon the injured vascular tissue, as well as to the downstream cardiac tissues, thereby protecting the entire cardiovascular system during the revascularization process. Limited preliminary experiments have shown very promising results, suggesting "minimal risk with high return" for the development of this innovative approach to treating both restenosis and ischemia/reperfusion injury at the same time. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death, and one of the primary causes of disability worldwide. Atherosclerosis is the primary contributor to this disease. Patients suffering from the disease are often treated using angioplasty and stent placement. Unfortunately, restenosis continues to be a long-term complication of these procedures due to vascular smooth muscle cell proliferation and migration. We have recently identified a novel compound that inhibits the growth of highly proliferative cells through a mechanism that has been proposed as a target to prevent vascular remodeling and restenosis. We, therefore, intend to test this idea using the new compound in a pig model of cardiovascular disease. In addition, about one-half of the deaths attributed to cardiovascular disease are due to acute cardiac events, including heart attack. The new compound, which includes a pro-nitroxyl functional group, could also be used to provide antioxidant protection to the heart, preventing additional damage during the reperfusion period following a heart attack. We propose to investigate the development of this multimodal approach to prevent the debilitating post- revascularization cardiovascular events.