Role of Hydrogen Sulfide and Oxidative Stress in Methamphetamine-Induced Cardiac Arrhythmias

硫化氢和氧化应激在甲基苯丙胺诱发的心律失常中的作用

• 批准号: 10331754
• 负责人: Paari Dominic
• 金额: $ 21.54万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331754
• 关键词: Action Potentials; Animals; Arrhythmia; Biological Availability; Biology; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cardiovascular Diseases; Catecholamines; Cause of Death; Cystathionine; Data; Electrophysiology (science); Enzymes; Fibrosis; Genetic; Heart; Heart Atrium; Heart Ventricle; Hydrogen Sulfide; Impaired cognition; Infusion procedures; Lyase; Mammals; Measures; Mediating; Methamphetamine; Mitochondria; Mus; Oxidation-Reduction; Oxidative Stress; Oxides; Pharmacology; Phenotype; Production; Reactive Oxygen Species; Role; Ryanodine Receptor Calcium Release Channel; Saline; Sulfides; Superoxides; Testing; Tissues; Transgenic Mice; Ventricular; Ventricular Arrhythmia; Wild Type Mouse; behavior test; methamphetamine effect; methamphetamine use; methamphetamine user; mouse model; novel; oxidant stress; psychologic; sudden cardiac death

Cardiovascular disease, specifically sudden cardiac death represents the most common cause of death among methamphetamine (METH) users but precise mechanism is unknown. Preliminary data in this proposal using a novel small animal electrophysiology set up shows that METH infusion in mice decreases atrial and ventricular hydrogen sulfide (H2S) levels and increases inducible atrial and ventricular arrhythmias. This proposal tests the hypothesis that METH use enhances reactive oxygen species production in the heart through altered H2S production, resulting in structural and electrical remodeling in the atria and ventricles of the heart leading to atrial and ventricular arrhythmias. To achieve this long-term objective, the role of H2S in METH associated electrical and structural remodeling in the heart will be evaluated by analyzing arrhythmia phenotype, action potential duration and fibrosis in METH infused Cystathionine γ-lyase (CSE, the predominant enzyme responsible for H2S production in mammals)transgenic mice and wild type (WT) mice supplemented with sulfide, compared to WT mice. In addition, the effect of oxidative stress in METH-associated electrical and structural remodeling in the heart will be assessed by measuring tissue and mitochondrial super-oxide levels in the atria and ventricles of METH and saline treated mice and by measuring the effect of METH on the arrhythmia phenotype and structural and electrical remodeling in pharmacological and genetic mouse models of oxidant stress inhibition. Furthermore, the role of calcium calmodulin kinase II (CaMKII) and Ryanodine receptor (RyR2) on METH induced oxidative stress mediated cardiac arrhythmias will be evaluated by measuring phosphorylated and oxidized CaMKII and RyR2 in the heart tissue of METH and saline treated WT mice, CSE-Tg mice and pharmacological and genetic mouse models of oxidant stress inhibition. Finally, the relationship between METH use, resultant catecholamine levels, H2S bioavailability, oxidative stress, psychological and cognitive dysfunction and cardiac arrhythmias will be evaluated by correlating cardiac arrhythmias to H2S levels, and scores on behavioral tests in METH and saline treated WT and CSE Tg mice.

心血管疾病，特别是心源性猝死是甲基苯丙胺（METH）使用者最常见的死亡原因，但确切的机制尚不清楚。该提案中使用新型小动物电生理学设置的初步数据显示，小鼠中的METH输注降低了心房和心室硫化氢（H2S）水平，并增加了可诱导的心房和室性心律失常。该提案检验了以下假设：METH的使用通过改变H2S的产生来增强心脏中活性氧的产生，导致心脏心房和心室的结构和电重构，从而导致房性和室性心律失常。为了实现这一长期目标，将通过分析METH输注的胱硫醚γ-裂解酶（CSE，哺乳动物中负责产生H2S的主要酶）转基因小鼠和补充硫化物的野生型（WT）小鼠中的心律失常表型、动作电位持续时间和纤维化，与WT小鼠相比，评价H2S在METH相关的心脏电和结构重塑中的作用。此外，通过测量METH和盐水处理的小鼠的心房和心室中的组织和线粒体超氧化物水平，以及通过测量METH对氧化应激抑制的药理学和遗传小鼠模型中的心律失常表型和结构和电重塑的影响，评估氧化应激在心脏中的METH相关的电和结构重塑中的作用。此外，将通过测量METH和盐水处理的WT小鼠、CSE-Tg小鼠以及氧化应激抑制的药理学和遗传学小鼠模型的心脏组织中的磷酸化和氧化的CaMKII和RyR 2来评价钙钙调蛋白激酶II（CaMKII）和RyR 2对METH诱导的氧化应激介导的心律失常的作用。最后，将通过将心律失常与H2S水平以及METH和盐水处理的WT和CSE Tg小鼠中的行为测试评分相关联来评估METH使用、所得的儿茶酚胺水平、H2S生物利用度、氧化应激、心理和认知功能障碍与心律失常之间的关系。