Oxidative Stress and Left Ventiricular Diastolic Function

项目3首席调查员/方案主任(最后第一，中)：哈里索普，大卫·G 项目3 氧化应激与左室舒张功能 项目负责人：小塞缪尔·C·达德利，医学博士，博士。 共同调查者：David L.Geenen，博士； 谢尔盖·迪卡洛夫，博士。 摘要 大约一半的心力衰竭病例发生在收缩功能保留的患者中，使舒张期 心力衰竭是一个严重的健康问题.舒张性功能障碍的患病率一直在增加， 死亡率与收缩期心力衰竭患者大致相同，而且，与收缩期心脏不同 失败，死亡率没有受到目前的治疗方法的影响。这在一定程度上源于缺乏机械性。 对这种情况的了解。然而，高血压是舒张压的主要危险因素之一。 功能障碍，这一应用将探索高血压可能导致舒张压下降的可能机制 功能障碍。一氧化氮(NO)已被证明可以增强舒张期的舒张性。高血压会导致 氧化应激通过一氧化氮合酶(NOS)解偶联导致NO损失，这是一种情况 以四氢生物蝶呤(BH4)的丢失为特征。BH4是一氧化氮合酶电子传递中的关键辅助因子 链条。当BH4被氧化时，解偶联的一氧化氮合酶发生。去偶联时，一氧化氮合酶产生超氧化物 而不是不。因此，少量的氧化应激会导致一个正反馈循环，最终 消耗最多的不是合成能力。最近，我们已经证明，BH4优先被 过氧亚硝酸盐和NAD(P)H氧化酶(NOX)衍生的过氧亚硝酸盐是一氧化氮合酶解偶联的中心。血管紧张素 已知II(Ang11)可以激活NOx，它似乎是初始氧化应激的来源，导致 进行性一氧化氮合酶解偶联，提示肾素-血管紧张素系统在一氧化氮合酶解偶联中的作用。基于 高血压和舒张期功能障碍的强烈临床相关性，我们发展了一种小鼠模型 用脱氧皮质酮醋酸盐诱导的高血压小鼠的舒张期功能障碍。我们已经展示了 这个模型通过氮氧化物依赖的机制产生氧化应激。在初步研究中，我们 显示这些小鼠心脏氧化应激，BH4减少，解偶联内皮型一氧化氮合酶(ENOS)，以及 超声心动图和血流动力学检测舒张期功能不全。膳食中添加BH4 预防或逆转eNOS解偶联和舒张期功能障碍的发生，提示一氧化氮合酶解偶联 可能在这种形式的高血压引起的舒张期功能障碍的发病机制中起中心作用。 因此，我们假设，在高血压期间，持续过量的活性氧产生。 导致恶性循环，其中过量的活性氧物种产生导致氧化耗尽 心肌BH4和NOS解偶联，这反过来又使过量产生的超氧化物持久存在，进一步 消耗BH4，降低心肌NO生物利用度。心脏中NO生物利用度的降低会导致 心肌细胞舒张期松弛功能受损。此外，我们将测试是否，在血管系统中，如果 NOx是产生初始一氧化氮合酶解偶联所必需的活性氧物种的中心。我们将测试 清除活性氧是否能防止BH4耗竭、非偶联一氧化氮合酶和舒张压 功能障碍。最后，由于一氧化氮合酶依赖血管紧张素转换酶，心脏血管紧张素转换酶似乎在舒张压中起作用。 功能障碍，血管紧张素转换酶抑制剂改善盐敏感型高血压大鼠模型的舒张期功能障碍 心脏肾素-血管紧张素系统(RAS)模型显示，在没有高血压的情况下，舒张期功能障碍， 我们将测试旨在减少肾素-血管紧张素系统激活的药物治疗是否会 预防BH4耗竭、非偶联一氧化氮合酶和舒张期功能障碍。 相关性：心力衰竭是美国一个主要且日益严重的公共健康问题，影响着约500万人 这个国家的病人。多项研究证实，多达一半的心力衰竭是由舒张期引起的。 功能障碍。收缩功能保留的舒张期功能不全的患病率正在增加。在患者中&GT； 舒张期功能不全70年，5年死亡率和1年住院率分别为50%和50%， 分别进行了分析。尽管患病率不断上升，并对预期寿命产生不祥的影响，但仍有 目前还没有批准的治疗方法来减缓舒张期功能障碍的进展，部分原因是我们的整体状况不佳 对舒张期功能障碍潜在机制的理解。这个项目将调查一部小说 潜在的机制可能为这种鲜为人知的疾病的新疗法开辟道路。 PHS 398/2590(09/04版，2006年4月4日重新发布)第152页延续格式页 首席调查员/项目主任(最后、第一、中间)：哈里森，大卫·G 初始预算期间的详细预算，从 直接成本仅12/01/08 11/30/09

Project 3 Principal Investigator/ProgramDirector (Last. First, Middle): HarriSOP, David G. PROJECT 3 Oxidative Stress and Left Ventricular Diastolic Function PROJECT LEADER: Samuel C. Dudley, Jr., M.D., Ph.D. CO-INVESTIGATORS: David L. Geenen, Ph.D.; Sergey Dikalov, Ph.D. ABSTRACT Approximately half of all heart failure cases occur in patients with preserved systolic function, making diastolic heart failure a substantial health problem. The prevalence of diastolic dysfunction has been increasing, the mortality rate is roughly equivalent to that of patients with systolic heart failure, and, unlike in systolic heart failure, mortality has been unaffected by current therapies. In part, this stems from a lack of mechanistic understanding about this condition. Nevertheless, hypertension is among the leading risk factors for diastolic dysfunction, and this application will explore a possible mechanism whereby hypertension may cause diastolic dysfunction. Nitric oxide (NO)has been shown to enhance diastolic relaxation. Hypertension results in an oxidative stress that leads to loss of NO through nitric oxide synthase (NOS) uncoupling, a condition characterized by the loss of tetrahydrobiopterin (BH4). BH4 is a critical co-factor in the NOS electron transport chain. Uncoupled NOS occurs when BH4 becomes oxidized. When uncoupled, NOS produces superoxide rather than NO. Therefore, a small amount of oxidant stress can lead to a positive feedback loop that ultimately depletes most NO synthetic capacity. Recently, we have shown that BH4 is preferentially oxidized by peroxynitrite and that NAD(P)H oxidase (NOX)-derived peroxynitrite is central to NOS uncoupling. Angiotensin II (Angll) is known to activate NOXs, which appear to be a source for the initial oxidant stress resulting in progressive NOS uncoupling, suggesting a role for the renin-angiotensin system in NOS uncoupling. Based on the strong clinical association of hypertension and diastolic dysfunction, we developed a murine model of diastolic dysfunction using mice with deoxycorticosterone acetate-salt induced hypertension. We have shown that this model generates oxidative stress through an NOX-dependent mechanism. In preliminary studies, we show these mice have cardiac oxidative stress, reduced BH4, uncoupled endothelial NOS (eNOS), and diastolic dysfunction by echocardiographic and hemodynamic measures. Dietary supplementation with BH4 prevents or reverses the onset of eNOS uncoupling and diastolic dysfunction, suggesting that NOS uncoupling may play a central role in the pathogenesis of diastolic dysfunction induced by this form of hypertension. Therefore, we hypothesize that persistent overproduction of reactive oxygen species during hypertension results in a vicious cycle where excess reactive oxygen species production leads to oxidative depletion of myocardial BH4and NOS uncoupling, which in turn perpetuates the overproduction of superoxide, further depleting BH4 and reducing myocardial NO bioavailability. A decreased NO bioavailability in the heart results in impaired diastolic relaxation of cardiomyocytes. Furthermore, we will test whether, as in the vasculature, if NOXs are central to generating the reactive oxygen species necessary for initial NOS uncoupling. We will test whether scavenging of reactive oxygen species will prevent BH4 depletion, uncoupled NOS, and diastolic dysfunction. Finally, since NOXs are Angll-dependent, cardiac Angll seems to play a role in diastolic dysfunction, Angll inhibitors ameliorate diastolic dysfunction in a salt-sensitive hypertensive rat model, and a model of cardiac renin-angiotensin system (RAS) shows diastolic dysfunction in the absence of hypertension, we will test whether pharmacological therapy targeting at reducing renin-angiotensin system activation will prevent BH4depletion, uncoupled NOS, and diastolic dysfunction. Relevance: Heart failure is a major and growing public health problem in the United States affecting ~5 million patients in this country. Multiple studies have confirmed that up to half of all heart failure results from diastolic dysfunction. The prevalence of diastolic dysfunction with preserved systolic function is increasing. In patients > 70 years with diastolic dysfunction, the 5-year mortality rate and 1-year hospitalization rates are 50% and 50%, respectively. Despite the increasing prevalence and ominous implications for life expectancy, there are currently no approved therapies to slow the progression of diastolic dysfunction, in part due to our overall poor understanding of the mechanisms underlying diastolic dysfunction. This project will investigate a novel potential mechanism that might open the way for new therapies for this poorly understood disorder. PHS 398/2590 (Rev.09/04, Reissued 4/2006) Page 152 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Harrison, David G. DETAILED BUDGET FOR INITIAL BUDGET PERIOD FROM THROUGH DIRECT COSTS ONLY 12/01/08 11/30/09