PTENuating Restenosis: An Innovative PTEN Promoter for Cardioprotection

PTENuating 再狭窄：用于心脏保护的创新 PTEN 启动子

• 批准号: 7579242
• 负责人: PERIANNAN KUPPUSAMY
• 金额: $ 18.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579242
• 关键词: Acute; Angioplasty; Animal Model; Animals; Antioxidants; Atherosclerosis; Attenuated; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cell Proliferation; Cells; Cessation of life; Cholesterol Esters; Chromosomes, Human, Pair 10; Complication; Coronary Arteriosclerosis; Coronary Vessels; Development; Disease; Evaluation; Event; Family suidae; Growth; Health; Heart; High Density Lipoproteins; Histologic; Hyperplasia; Incidence; Injury; Intervention; LDL Cholesterol Lipoproteins; Lead; Modeling; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; PTEN gene; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Procedures; Process; Proteins; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Role; Smooth Muscle Myocytes; Stents; Testing; Time; Tissues; Up-Regulation; Vascular remodeling; Wound Healing; base; cell motility; coronary angioplasty; disability; functional group; in vivo; inhibitor/antagonist; injured; innovation; migration; minimal risk; nitroxyl; novel; novel strategies; percutaneous coronary intervention; prevent; promoter; public health relevance; research study; response; restenosis; vascular smooth muscle cell proliferation

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.

描述（由申请人提供）：心血管疾病是世界范围内死亡的主要原因，也是导致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。大约一半的心血管疾病死亡是由急性心脏事件引起的，包括心肌梗塞。患者通常通过经皮冠状动脉介入治疗进行治疗，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）是此类手术的主要限制。 PTEN（从 10 号染色体上删除的磷酸酶和张力蛋白同源物）已被提议作为抑制血管成形术后血管平滑肌细胞 (SMC) 增殖和迁移的潜在靶点，从而导致病理性血管重塑和再狭窄。我们最近发现了一类新型化合物，它们通过上调 PTEN 水平来选择性抑制高度增殖的细胞。因此，我们假设这些新化合物可能有效减轻再狭窄。此外，氧化应激被认为是经皮冠状动脉介入手术后新内膜增生的一个因素。我们提出了另一个假设，即这些化合物可以进一步修饰以包含硝酰基前官能团，这可以减少对受损血管组织以及下游心脏组织施加的氧化应激，从而在治疗过程中保护整个心血管系统。血运重建过程。有限的初步实验已经显示出非常有希望的结果，表明开发这种同时治疗再狭窄和缺血/再灌注损伤的创新方法具有“风险最小、回报高”的特点。公共卫生相关性：心血管疾病是导致死亡的主要原因，也是全世界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采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，它通过一种被提议作为预防血管重塑和再狭窄的靶标的机制来抑制高度增殖细胞的生长。因此，我们打算在猪心血管疾病模型中使用这种新化合物来测试这一想法。此外，大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）造成的。这种包含硝酰基前官能团的新化合物还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开发，以预防血运重建后使人衰弱的心血管事件。