Novel Regulatory Mechanisms in the Human Microcirculation

人体微循环的新型调节机制

• 批准号: 9251564
• 负责人: David D. Gutterman
• 金额: $ 42.12万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-12 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251564
• 关键词: 3-methyladenine; Acute; Adipose tissue; Atherosclerosis; Attenuated; Autophagocytosis; Blood Vessels; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Physiology; Cell physiology; Ceramides; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Dilator; Disease; Endothelial Cells; Endothelium; Genes; Goals; Health; Human; Hydrogen Peroxide; Hydrolysis; Impairment; In Vitro; Individual; Inflammation; Injury; Link; Linkage Disequilibrium; Lysophosphatidic Acid Receptors; Maintenance; Mediating; Mediator of activation protein; Messenger RNA; Microcirculation; Microvascular Dysfunction; Mitochondria; Oxidation-Reduction; Pathology; Pathway interactions; Patients; Phospholipids; Phosphoric Monoester Hydrolases; Play; Population; Process; Production; Reactive Oxygen Species; Receptor Activation; Risk; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Small Interfering RNA; Stress; System; Telomerase; Testing; Tissues; Toxic effect; Vascular Diseases; Vasodilator Agents; arteriole; attenuation; bafilomycin A1; base; gene product; inhibitor/antagonist; lipid phosphate phosphatase; lysophosphatidic acid; lysophosphatidic acid phosphatase; novel; overexpression; paracrine; pressure; prevent; receptor; response; shear stress; stressor; vascular inflammation

Project Abstract The microvasculature plays a critical role in the development and consequences of a broad range of cardiovascular diseases. The main assessment of microvascular function is via endothelium-dependent NO- mediated dilation which is reduced as a precursor to coronary artery disease (CAD) and cardiomyopathy. In human arterioles from subjects with CAD loss of NO-mediated flow-mediated dilation (FMD) is compensated by hydrogen peroxide (H2O2) from endothelial mitochondria. Although both are dilators, NO and H2O2 have opposing effects on vascular health, with NO promoting quiescence and H2O2 promoting vascular and parenchymal inflammation leading to atherosclerosis. Understanding mechanisms responsible for this switch in mediator may be key to minimizing tissue stress or injury from vascular paracrine redox toxicity. The goal of this study is to determine fundamental cellular pathways regulating this switch from NO to H2O2. We propose that two systems, recently shown to be shear sensitive and fundamental to cell function are linked as critical for FMD in human arterioles (HA). The first is autophagy which we propose is the controlling switch that regulates shear-induced production of NO or H2O2. Blocking autophagic flux reduces NO and enhances reactive oxygen species (ROS). The second pathway involves lipid phosphate phosphatase 3 (LPP3), which responds to shear by inhibiting lysophosphatidic acid (LPA), lowering ROS and promoting NO. A single nucleotide polymorphism of this gene, seen in 80% of the population is associated with heightened risk for CAD. We propose that shear-induced activation of LPP3 is needed to maintain NO-mediated FMD in HA. Neither LPP3 nor autophagy has been linked to the mediator of FMD. We will study fresh human coronary and adipose arterioles in human microvascular endothelial cells in vitro using stimulators and inhibitors of autophagy and LPA to determine their role in FMD. The local tissue impact can be profound given the different effect of NO vs. H2O2 on cardiovascular function. We will test the following hypotheses: Hypothesis 1. Autophagy is critical in maintaining NO as the mediator of FMD in the human coronary microcirculation. Reduced autophagy leads to a switch to H2O2 as the mediator of FMD. Hypothesis 2. LPP3 is upregulated by microvascular endothelial shear resulting in LPA hydrolysis, attenuation of endothelial ROS, with maintenance of NOS-dependent FMD. If LPP3 is mechanistically linked to microvascular dysfunction, this could be an important target, either directly or through LPA, for reducing the vascular inflammation in a large number of genetically CAD-susceptible individuals.

项目摘要