Regulatory Mechanisms of Oxidative Stress in Hypertensive Heart Disease

高血压性心脏病氧化应激的调节机制

• 批准号: 8269851
• 负责人: KARL T WEBER
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269851
• 关键词: 4 hydroxynonenal; Accounting; Address; Adrenergic beta-Antagonists; Aldosterone; Amlodipine; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Appearance; Biochemical; Biological Markers; Biological Preservation; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Death; Cell Survival; Cells; Cicatrix; Coupled; Cuprozinc Superoxide Dismutase; Cyclosporine; Depressed mood; Drug Metabolic Detoxication; Equilibrium; Event; Fibrosis; Flavonoids; Gene Expression Profile; Generations; Genes; Harvest; Health; Heart; Heart failure; Hormones; Hydrogen Peroxide; Hypocalcemia result; Inflammatory; Injury; Intervention; Ionophores; Lead; Left; Link; Lipid Peroxidation; Mediating; Membrane Potentials; Metallothionein; Mitochondria; Modeling; Molecular; Molecular Mimicry; Muscle; Myocardial; Myocardium; NF-kappa B; Necrosis; Nitrogen; Organelles; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Oxygen; Parathyroid gland; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plant Roots; Predisposition; Prevention; Production; Property; Proteome; Pump; Quercetin; Rattus; Reactive Oxygen Species; Reagent; Regulation; Respiratory Chain; Risk; Risk Factors; Role; Serum; Side; Signal Transduction; Signal Transduction Pathway; Site; Sodium Chloride; Source; Staging; Sterility; Stimulus; Structure; Time; Tissues; Transducers; Transforming Growth Factors; Troponin; Up-Regulation; Work; attenuation; base; carvedilol; channel blockers; cyclophilin D; endoplasmic reticulum stress; glutathione synthase; hypertensive heart disease; inhibitor/antagonist; injury prevention; isoprostaglandin F2alpha type-III; mitochondrial membrane; mitochondrial permeability transition pore; mitogen-activated protein kinase p38; novel; outcome forecast; oxidative damage; pre-clinical; prevent; prolinedithiocarbamate; public health relevance; response; response to injury; sensor; tissue repair; transcription factor MTF-1

DESCRIPTION (provided by applicant): Hypertensive heart disease (HHD) has its pathophysiologic origins arising from the reparative fibrosis, or scarring, that replaces necrotic cardiomyocytes. Understanding the pathobiology behind cardiomyocyte necrosis will lead to the prevention of HHD while the availability of biomarkers predictive of necrosis and obtained noninvasively from peripheral blood mononuclear cells (PBMC) will aid in identification of risk. In addressing these objectives we use our established model of HHD provoked by aldosterone/salt treatment (ALDOST) and exploit its preclinical (wk 1) and pathologic (wk 4) stages. Central hypothesis: in HHD, fibrosis at wk 4 is due to oxidative stress- induced cardiomyocyte necrosis, where the cell's altered redox state is rooted in parathyroid hormone (PTH)- mediated intracellular Ca2+ overloading, including cardiac myocytes and mitochondria and PBMC, and where the rate of reactive oxygen species (ROS) generation overwhelms the rate of their detoxification by endogenous antioxidant defenses. This 2C+-adependent induction of oxidative stress promotes the opening of the mitochondrial permeability transition pore (mPTP) to culminate i n necrosis. This prooxidant state can be counterbalanced by the contemporaneous rise in cytosolic and mitochondrial 2Z+nserving as antioxidant. We hypothesize the dysequilibrium between pro- and antioxidant is inextricably linked to the coupled dyshomeostasis of Ca2+ and Zn2+. Mitochondria are the major source of ROS. Aim #1: to determine the cellular and molecular origins of oxidative stress arising from intracellular C2+a overloading and the role of intra mitochondrial Ca2+ accumulation, oxidative stress and mPTP opening in the signal-transduction pathway leading to necrosis and to compare heart tissue and its cardiac myocytes and mitochondria with PBMCW.e use mitochondria-targeted reagents: to b lock the 2+Cau niporter; t o serve as antioxidant; and to inhibit mPTP. Necrosis is prevented by increased [Zn2+]i, which induces its sensor, metal-responsive transcription factor (MTF)-1 and the antioxidant genes it regulates. Such "uncoupling therapy" includes: Zn4SOsupplement; PDTC, a Zn2+ ionophore; or ZnSO4 plus a mlodipine. Aim # 2: to explore the signal-transduction antioxidant pathway invoked by increased intracellular [Zn2+]i and promoted by ZnSO4, PDTC, or ZnSO4 with amlodipine, along with the role of MTF-1 regulated antioxidant defenses that eventuate in an antioxidant, anti-inflammatory phenotype in cardiac myocytes and to compare heart tissue and its cardiomyocytes and mitochondria with PBMC. PBMC share common pathophysiologic responses and upregulated gene networks with cardiac myocytes and mitochondria during ALDOST. We harvest PBMC throughout Aims #1 and 2 in search of novel surrogate biomarkers of risk, injury and response to intervention. Aim #3: i) to identify major components of the PBMC transcriptome and proteome having molecular mimicry with the pro inflammatory cardiac phenotype, including its mitochondrial proteome, and ii) to elucidate specific pathway candidates that could serve as noninvasive biomarkers predictive of risk during preclinical and pathologic stages of HHD. PUBLIC HEALTH RELEVANCE: Heart failure is a major health problem. Hypertensive heart disease (HHD), a major factor contributing to the heart's failure as a muscular pump, involves an adverse structural remodeling of myocardium related to fibrosis. Our aim is to better understand mechanisms contributing to the appearance of fibrosis and to thereby identify risk and prevention of HHD.

描述（由申请人提供）：高血压心脏病（HHD）的病理生理起源是由修复性纤维化或疤痕所产生的，它取代了坏死性心肌细胞。了解心肌细胞坏死背后的病理生物学将导致预防HHD，而生物标志物可预测坏死的可用性，并从外周血单核细胞（PBMC）中获得无创的性能，有助于鉴定风险。在解决这些目标时，我们使用了通过醛固酮/盐处理（Aldost）引起的既定HHD模型，并利用其临床前（WK 1）和病理学（WK 4）阶段。中心假设：在HHD中，WK 4处的纤维化是由于氧化应激诱导的心肌细胞坏死，其中细胞改变的氧化还原状态植根于甲状旁腺激素（PTH） - 介导的细胞内CA2+过度载荷，包括心肌和pBmc（ROS）的速率（ROS）（ROS）（ROS）（ROS）（ROS），该率是有效的（ROS）。内源性抗氧化剂防御的排毒。氧化应激的这种2C+依赖性诱导促进了线粒体通透性过渡孔（MPTP）的开放，从而达到了坏死。这种抗氧化剂的胞质和线粒体2z+NServing作为抗氧化剂的同时升高可以抵消这种潜在的状态。我们假设促氧化剂和抗氧化剂之间的Dysequesilibrium与Ca2+和Zn2+的耦合Dyshomeostasis密不可分。线粒体是ROS的主要来源。目的1：确定由细胞内C2+ A过载引起的氧化应激的细胞和分子起源，以及线粒体内CA2+积累的作用，氧化应激，MPTP在信号转移途径中开放，导致NECROSIS，导致心脏组织和其心脏组织肌肉核心和斑纹的肌肉核心和斑纹。试剂：B锁定2+Cau niporter；用作抗氧化剂；并抑制MPTP。 [Zn2+] i的增加可预防坏死，从而诱导其传感器，金属响应转录因子（MTF）-1和它调节的抗氧化剂基因。这种“解偶联疗法”包括：Zn4Sosupplement; PDTC，Zn2+离子载体；或znso4加上mlodipine。 Aim # 2: to explore the signal-transduction antioxidant pathway invoked by increased intracellular [Zn2+]i and promoted by ZnSO4, PDTC, or ZnSO4 with amlodipine, along with the role of MTF-1 regulated antioxidant defenses that eventuate in an antioxidant, anti-inflammatory phenotype in cardiac myocytes and to compare heart tissue and its带有PBMC的心肌细胞和线粒体。 PBMC在aldost期间与心肌细胞和线粒体共享常见的病理生理反应和上调基因网络。我们在整个目标＃1和2中收集PBMC，以寻找新型的替代生物标志物的风险，伤害和对干预的反应。目的＃3：i）确定具有分子模仿的PBMC转录组和蛋白质组的主要组成部分，其中包括炎症性心脏表型，包括其线粒体蛋白质组，以及ii），以阐明可以作为无创生物标记的特定途径候选，以预测在预先利用的生物标志性的风险中，并在预先利用的风险中预测了HHD的途径。 公共卫生相关性：心力衰竭是一个主要的健康问题。高血压心脏病（HHD）是导致心脏作为肌肉泵失败的主要因素，涉及与纤维化相关的心肌的不良结构重塑。我们的目的是更好地了解有助于纤维化出现的机制，从而确定HHD的风险和预防。