Project 10 - The role of nanoformulated Cu/ZnSOD in reducing systemic hypertensi

项目 10 - 纳米配方 Cu/ZnSOD 在降低全身性高血压中的作用

• 批准号: 8730202
• 负责人: Saraswathi Viswanathan
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8730202
• 关键词: 3-nitrotyrosine; Address; Adipose tissue; Adverse effects; Antihypertensive Agents; Antioxidants; Attention; Biodistribution; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cell Death; Cessation of life; Chronic; Conscious; Data; Development; Diet; Disease; Effectiveness; Endothelial Cells; Enzymes; Event; Excision; Fatty acid glycerol esters; Functional disorder; Generations; Goals; Half-Life; Healthcare; Heart failure; Human; Hypertension; Individual; Inflammation; Inflammation Mediators; Inflammatory; Label; Lead; Link; Linoleic Acids; Liver; Lodine; Measures; Mediating; Metabolic Diseases; Modeling; Molecular; Mus; Nanotechnology; Nebraska; Nonesterified Fatty Acids; Obese Mice; Obesity; Organ; Oxidative Stress; Pharmacotherapy; Physiological; Plasma; Process; Production; Proteins; Research; Resistance; Risk; Risk Factors; Role; Spleen; Stimulus; Stroke; Superoxides; Techniques; Therapeutic; Therapy Clinical Trials; Thrombosis; Tissues; Toxic effect; Vascular Endothelial Cell; Visceral; Wild Type Mouse; antioxidant therapy; cardiovascular disorder risk; cardiovascular risk factor; clinically relevant; copper zinc superoxide dismutase; design; enzyme therapy; feeding; in vivo; insight; nanomedicine; new therapeutic target; novel; polyethylene glycol-superoxide dismutase; prevent; research study; response; single photon emission computed tomography

Although oxidative stress is a prevalent condition in obesity, the role of oxidative stress initiated by superoxide in modulating adipose tissue (AT)-specific inflammation in obesity remains unclear. Moreover, the potential role of antioxidants in modulating the inflammatory state of obese AT and subsequent development of systemic hypertension is unknown. Our preliminary data show that pretreatment of human aortic endothelial cells with nanoformulated copper/zinc superoxide dismutase (nanoSOD) but not native or PEG-SOD reduces linoleic acid-induced superoxide production. Our in vivo data show that nanoSOD reduces superoxide-mediated oxidative stress in obese AT as evident from decreased nitrotyrosine content in the AT stromal vascular fraction. Because oxidative stress is often associated with inflammation and because AT-specific inflammation mediates the pathological consequence of obesity, we hypothesize that reduction of AT superoxide using nanoSOD will lead to reduced AT-inflammation which, in turn, will lead to reduced systemic hypertension in obesity. The studies proposed in this application will take physiological, pharmacological, and molecular approaches to investigate how reduction of superoxide using nanoSOD in obesity will impact the development of systemic hypertension. Because endothelial cell oxidative stress is an underlying event linking obesity and hypertension, we will determine the role of nanoSOD in delivering active SOD to endothelial cells and in scavenging free fatty acid-induced superoxide in Specific Aim 1. In Specific Aim 2, we will determine the biodistribution of SOD delivered as nanoSOD in a model of diet induced obesity. Wild type mice will be fed a high fat diet (45% fat) for 12 wk and injected with 1251-labelled nanoSOD. SPECT imaging will be carried out to determine the biodistribution of SOD in tissues including visceral AT, liver, and spleen. In Specific Aim 3, we will determine the toxicity of nanoSOD in a model of diet-induced obesity. We will also study the effectiveness of nanoSOD in scavenging superoxide from AT and in reducing systemic hypertension in obesity. Briefly, after 12 wk on high fat diet, the mice will receive the nanozymes for 2 wk. At the end of 14 wk, we will analyze AT superoxide, AT-inflammation and systemic hypertension. The findings will be relevant to determining the therapeutic potential of nanoformulated antioxidant enzymes in treating chronic cardiovascular risk factors in obesity.

虽然氧化应激是肥胖症的一种常见疾病，但由超氧化物引发的氧化应激在调节肥胖症中脂肪组织（AT）特异性炎症中的作用仍不清楚。此外，抗氧化剂在调节肥胖AT的炎症状态和随后的全身性高血压发展中的潜在作用尚不清楚。我们的初步数据表明，预处理的人主动脉内皮细胞与纳米铜/锌超氧化物歧化酶（nanoSOD），而不是本地或PEG-SOD减少亚油酸诱导的超氧化物的产生。我们的体内数据表明，nanoSOD减少了超氧化物介导的氧化应激在肥胖AT明显减少硝基酪氨酸含量在AT基质血管部分。因为氧化应激通常与炎症相关，并且因为AT特异性炎症介导肥胖的病理后果，我们假设使用nanoSOD减少AT超氧化物将导致AT炎症减少，这反过来将导致肥胖症中全身性高血压减少。本申请中提出的研究将采用生理学、药理学和分子方法来研究肥胖症患者使用nanoSOD减少超氧化物将如何影响全身性高血压的发展。由于内皮细胞氧化应激是一个潜在的事件联系肥胖和高血压，我们将确定nanoSOD在提供活性SOD的内皮细胞和清除游离脂肪酸诱导的超氧化物在特定目标1的作用。在具体目标2中，我们将确定作为纳米SOD递送的SOD在饮食诱导的肥胖模型中的生物分布。将野生型小鼠喂食高脂肪饮食（45%脂肪）12周，并注射1251标记的nanoSOD。将进行SPECT成像，以确定SOD在组织（包括内脏AT、肝脏和脾脏）中的生物分布。在具体目标3中，我们将确定nanoSOD在饮食诱导的肥胖模型中的毒性。我们还将研究nanoSOD在清除AT超氧化物和降低肥胖患者全身性高血压方面的有效性。简言之，在高脂肪饮食12周后，小鼠将接受纳米酶2周。在14周结束时，我们将分析AT超氧化物，AT炎症和全身性高血压。这一发现将有助于确定纳米抗氧化酶在治疗肥胖症慢性心血管危险因素方面的治疗潜力。