Differential mechanism of baroreflex dysfunction in atherosclerosis and aging

令人信服的证据表明，在动脉粥样硬化和衰老中，活性氧物种(ROS)导致神经元和心血管功能障碍。该项目的目标是明确ROS在这些状态下导致压力感受性反射功能障碍中的作用，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通过对传入的不同影响而损害压力感受器反射功能 以及反射的中心成分。在动脉粥样硬化中，缺陷可能主要发生在传入肢体，而随着年龄的增长，这两个部分都可能受损。动脉粥样硬化和衰老小鼠压力感受器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降压神经活动、肾交感神经活动、动脉压和心率，以及测量对药物引起的动脉压力变化和电刺激主动脉降压神经中压力感受器传入的反应来确定。ROS的作用将通过使用膜通透性超氧化物歧化酶/过氧化氢酶模拟物进行治疗，以及通过缺乏抗氧化剂分子(例如MnSOD和CuZnSOD)的转基因小鼠和过度表达抗氧化酶的转基因小鼠的研究来评估。需要检验的第二个假设是，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的来源。对转基因小鼠、腺病毒介导的基因转移和药物拮抗剂的研究将使我们能够选择性地操纵特定细胞类型的亚细胞室中的ROS，以揭示ROS的产生来源。此外，在分离自对照、动脉粥样硬化和衰老小鼠的压力感受器神经元的研究中，将直接评估神经元ROS的产生及其对膜兴奋性和离子电流的影响。这项拟议的研究有望对了解动脉粥样硬化患者和老年人压力感受器反射功能障碍的机制具有重要意义。这一结果可能特别适用于动脉粥样硬化在老年人中常见的人类。抗氧化剂疗法 目前在心血管疾病的预防和治疗中作为很有前途的药物受到了广泛的关注。从拟议的研究中获得的知识可能会影响未来抗氧化剂疗法的使用。

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.