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: 7985257
• 负责人: KARL T WEBER
• 金额: $ 37万
• 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/7985257
• 关键词: 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; Cyclosporins; Depressed mood; Drug Metabolic Detoxication; Equilibrium; Event; Fibrosis; Flavonoids; Gene Expression Profile; Generations; Genes; Harvest; Health; Heart; Heart failure; Hydrogen Peroxide; Hypocalcemia result; Inflammatory; Injury; Intervention; Ionophores; Lead; Left; Link; Lipid Peroxidation; Mediating; Membrane Potentials; Metallothionein; Metals; Mitochondria; Modeling; Molecular; Molecular Mimicry; Muscle; Myocardial; Myocardium; NF-kappa B; Necrosis; Nitrogen; Organelles; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Oxygen; Parathyroid Hormones; 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; Source; Staging; Sterility; Stimulus; Structure; Time; Tissues; Transducers; Transforming Growth Factors; Troponin; Up-Regulation; Work; Wound Healing; attenuation; base; carvedilol; channel blockers; cyclophilin D; endoplasmic reticulum stress; glutathione synthase; human PTH protein; 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; transcription factor; 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）的病理生理学起源是由替代坏死心肌细胞的修复性纤维化或疤痕形成引起的。了解心肌细胞坏死背后的病理学将有助于预防 HHD，而从外周血单核细胞 (PBMC) 中无创获得的预测坏死的生物标志物将有助于识别风险。为了实现这些目标，我们使用我们已建立的由醛固酮/盐治疗 (ALDOST) 引发的 HHD 模型，并利用其临床前（第 1 周）和病理（第 4 周）阶段。中心假设：在 HHD 中，第 4 周的纤维化是由于氧化应激诱导的心肌细胞坏死，其中细胞氧化还原状态的改变根源于甲状旁腺激素 (PTH) 介导的细胞内 Ca2+ 超载，包括心肌细胞、线粒体和 PBMC，并且其中活性氧（ROS）产生的速度超过了内源性抗氧化防御的解毒速度。这种 2C+ 依赖性氧化应激诱导促进线粒体通透性转换孔 (mPTP) 打开，最终导致坏死。这种促氧化状态可以通过细胞质和线粒体 2Z+n 作为抗氧化剂的同时增加来平衡。我们假设促抗氧化剂和抗氧化剂之间的不平衡与 Ca2+ 和 Zn2+ 的耦合失调有着千丝万缕的联系。线粒体是 ROS 的主要来源。目标#1：确定细胞内 C2+a 超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、氧化应激和 mPTP 在导致坏死的信号转导途径中开放的作用，并比较心脏组织和心肌组织其心肌细胞和线粒体与PBMCW.e使用线粒体靶向试剂：阻断2+Cau niporter；作为抗氧化剂；并抑制 mPTP。 [Zn2+]i 的增加可防止坏死，从而诱导其传感器、金属响应转录因子 (MTF)-1 及其调节的抗氧化基因。此类“解偶联疗法”包括： Zn4SO补充剂； PDTC，一种 Zn2+ 离子载体；或 ZnSO4 加氯地平。目标#2：探索细胞内 [Zn2+]i 增加所引发并由 ZnSO4、PDTC 或 ZnSO4 与氨氯地平促进的信号转导抗氧化途径，以及 MTF-1 调节的抗氧化防御的作用，最终形成抗氧化剂、抗氧化物质。 -心肌细胞的炎症表型，并将心脏组织及其心肌细胞和线粒体与 PBMC 进行比较。在 ALDOST 过程中，PBMC 与心肌细胞和线粒体具有共同的病理生理反应和上调的基因网络。我们在目标 #1 和目标 2 中收获 PBMC，以寻找风险、损伤和干预反应的新型替代生物标志物。目标#3：i) 鉴定与促炎性心脏表型具有分子拟态性的 PBMC 转录组和蛋白质组的主要成分，包括其线粒体蛋白质组，以及 ii) 阐明可作为临床前风险预测的非侵入性生物标志物的特定候选途径HHD 的病理阶段。 公共卫生相关性：心力衰竭是一个主要的健康问题。高血压性心脏病（HHD）是导致心脏作为肌肉泵功能衰竭的一个主要因素，涉及与纤维化相关的不利的心肌结构重塑。我们的目标是更好地了解导致纤维化出现的机制，从而识别 HHD 的风险和预防措施。