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.

尽管氧化应激在肥胖症中是一种普遍的疾病，但超氧化物在调节脂肪组织（AT）特定炎症中引发的氧化应激的作用尚不清楚。此外，抗氧化剂在调节肥胖的炎症状态和随后的系统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，用纳米成型的铜/锌超氧化物歧化酶（纳米编码）对人主动脉内皮细胞进行了预处理，但不能减少亚油酸诱导的超氧化物的产生。我们的体内数据表明，纳米编码可降低肥胖中的超氧化物介导的氧化应激，从而从AT基质血管级分中的硝基酪氨酸含量降低而明显。由于氧化应激通常与炎症有关，并且由于AT特异性炎症介导了肥胖的病理后果，因此我们假设使用纳米od减少AT AT AT AT AT AT会导致炎症减少，从而导致肥胖症的全身性高血压降低。本应用中提出的研究将采用生理，药理和分子方法来研究肥胖症中使用纳米码的超氧化物的减少将如何影响系统性高血压的发展。由于内皮细胞氧化应激是连接肥胖和高血压联系起来的基本事件，因此我们将确定纳米码在向内皮细胞传递活性SOD和清除特定目标中的自由脂肪酸诱导的超氧化物1的作用。在特定的目标2中，我们将确定nanosod在nanosod中的生物分布，在nanosod中的生物分布，在nanosod中均具有肥胖的模型。野生型小鼠将用于12周的高脂饮食（45％脂肪），并注入1251个标记的纳米码。将进行SPECT成像，以确定包括内脏，肝脏和脾脏在内的组织中SOD的生物分布。在特定的目标3中，我们将在饮食诱导的肥胖模型中确定纳米码的毒性。我们还将研究纳米编码在从AT和降低肥胖症中系统性高血压中清除超氧化物中的有效性。简而言之，在高脂肪饮食上12周后，小鼠将接受2周的纳米酶。在14周结束时，我们将在超氧化物，炎症和全身性高血压下进行分析。这些发现将与确定纳米成型抗氧化剂酶在治疗肥胖症中慢性心血管危险因素方面的治疗潜力有关。