Differential mechanism of baroreflex dysfunction in atherosclerosis and aging

动脉粥样硬化和衰老过程中压力反射功能障碍的差异机制

• 批准号: 6704849
• 负责人: MARK W CHAPLEAU
• 金额: $ 24.29万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-21 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704849
• 关键词: NAD(P)H dehydrogenase; aging; animal old age; antioxidants; atherosclerosis; baroreflex; free radical oxygen; laboratory mouse; membrane potentials; mitochondria; oxidative stress; superoxide dismutase; tissue /cell culture; vascular endothelium

Compelling evidence implicates reactive oxygen species (ROS) in causing neuronal and cardiovascular dysfunction in atherosclerosis and aging. The goals of the proposed project are to define the role of ROS in causing baroreflex dysfunction in these states and to determine effects of combined atherosclerosis and aging on baroreflex sensitivity. The first hypothesis to be tested is that ROS impair baroreflex function through differential effects on afferent and central components of the reflex. The defect may be primarily in the afferent limb in atherosclerosis, whereas both components may be impaired in aging. The relative importance of alterations in afferent and central components of the baroreflex in atherosclerotic and senescent mice will be determined through direct recordings of aortic depressor nerve activity, renal sympathetic nerve activity, arterial pressure and heart rate; and measurement of responses to drug-induced changes in arterial pressure and electrical stimulation ofbaroreceptor afferents in the aortic depressor nerve. The role of ROS will be assessed through treatment with membrane permeable superoxide dismutase/catalase mimetics and by studies of genetically-modified mice deficient in antioxidant molecules (e.g. MnSOD and CuZnSOD) and transgenics that over-express antioxidant enzymes. The second hypothesis to be tested is that the mechanism of the ROS-mediated decrease in baroreceptor sensitivity differs in atherosclerosis and aging. Vascular NAD(P)H oxidase is proposed as the source of ROS in atherosclerosis while mitochondria in baroreceptors are proposed as the source in aging. Studies in genetically-modified mice, adenoviral-mediated gene transfer, and pharmacological antagonists will enable selective manipulation of ROS in subcellular compartments in specific cell types to reveal the sources of ROS generation. Furthermore, neuronal ROS generation and its effects on membrane excitability and ionic currents will be directly assessed in studies of cultured baroreceptor neurons isolated from control, atherosclerotic and senescent mice. The proposed studies are expected to have important implications for understanding mechanisms of baroreflex dysfunction in patients with atherosclerosis and in the elderly. The results may be particularly relevant to humans where atherosclerosis is common in the elderly. Antioxidant therapies are currently receiving much attention as promising agents in the prevention and treatment of cardiovascular disease. Knowledge gained from the proposed studies may impact on future use of antioxidant therapies.

令人信服的证据表明，活性氧（ROS）在动脉粥样硬化和衰老中引起神经元和心血管功能障碍。该项目的目标是确定ROS在这些状态下引起压力反射功能障碍的作用，并确定动脉粥样硬化和衰老对压力反射敏感性的影响。 要检验的第一个假设是，ROS通过对传入神经的不同影响损害压力感受性反射功能。 和反射的中枢成分。 在动脉粥样硬化中，这种缺陷可能主要发生在传入支，而这两种成分在衰老中可能都受损。 动脉粥样硬化和衰老小鼠中压力感受器反射的传入和中枢成分改变的相对重要性将通过直接记录主动脉减压神经活动、肾交感神经活动、动脉压和心率来确定;并测量对药物诱导的动脉压变化和主动脉减压神经中压力感受器传入的电刺激的反应。ROS的作用将通过用膜渗透性超氧化物歧化酶/过氧化氢酶模拟物处理以及通过研究抗氧化分子（例如MnSOD和CuZnSOD）缺陷的转基因小鼠和过度表达抗氧化酶的转基因小鼠来评估。 第二个有待检验的假设是，ROS介导的压力感受器敏感性降低的机制在动脉粥样硬化和 衰老 血管NAD（P）H氧化酶被认为是动脉粥样硬化中ROS的来源，而压力感受器中的线粒体被认为是衰老中ROS的来源。 在基因修饰小鼠、腺病毒介导的基因转移和药理学拮抗剂中的研究将使在特定细胞类型的亚细胞区室中的ROS的选择性操纵成为可能，以揭示ROS产生的来源。 此外，神经元活性氧的产生及其对膜兴奋性和离子电流的影响将直接评估从对照，动脉粥样硬化和衰老小鼠分离的培养的压力感受器神经元的研究。 这些研究对了解动脉粥样硬化患者和老年人压力感受性反射功能障碍的机制具有重要意义。 这一结果可能与动脉粥样硬化在老年人中很常见的人类特别相关。 抗氧化剂治疗是 目前作为预防和治疗心血管疾病的有前途的药物受到广泛关注。 从拟议的研究中获得的知识可能会影响未来抗氧化治疗的使用。