Sudden cardiac arrest and circulating hydrogen sulfide

心脏骤停和循环硫化氢

• 批准号: 10396567
• 负责人: Nona Sotoodehnia
• 金额: $ 71.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396567
• 关键词: Accounting; Address; Adult; Anabolism; Animal Model; Animals; Apoptosis; Arrhythmia; Atherosclerosis; Biochemical; Biocompatible Materials; Biological; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Case-Control Studies; Cell Survival; Cell physiology; Cellular biology; Cessation of life; Clinical; Clinical assessments; Cohort Studies; Complex; Coronary Arteriosclerosis; Data; Dietary Factors; Disease; Drug Targeting; Electrophysiology (science); Environmental Pollutants; Enzymes; Erythrocyte Membrane; Etiology; Evaluation; Functional disorder; General Population; Genes; Genetic; Genetic Variation; Genomics; Health; Heart Arrest; Heart Hypertrophy; Heart Injuries; Heart failure; Homeostasis; Human; Hydrogen Sulfide; Hypoxia; Injury; Ischemia; Link; Measurement; Measures; Mediating; Mediation; Membrane; Mendelian randomization; Metabolism; Methodology; Molecular; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physical activity; Physiological; Plasma; Population; Population Study; Prevention; Property; Public Health; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Research Project Grants; Risk; Risk Factors; Role; Sampling; Signal Transduction; Signaling Molecule; Smoking; Stress; Tachyarrhythmias; Testing; Time; Tissues; Toxic effect; Transcriptional Regulation; Vasodilator Agents; Ventricular; Ventricular Fibrillation; cardioprotection; carotid intima-media thickness; case control; clinical material; combat; coronary artery occlusion; genomic data; heart function; improved; in vivo; innovation; ischemic injury; knock-down; modifiable risk; mortality; multidisciplinary; myocardial infarct sizing; new therapeutic target; novel; phenotypic data; population based; preservation; prevent; prospective; response; risk stratification; small hairpin RNA; study population; transcriptome; transcriptome sequencing

Project Summary Sudden cardiac arrest (SCA) continues to be a major public health concern, accounting for up to 400,000 annual deaths in the US alone. In Western populations, ventricular fibrillation is the most common electrophysiologic mechanism for SCA while coronary artery disease (CAD) is the most common underlying disease. Despite recent advances in treatment and prevention of CAD, SCA continues to be one of the leading causes of mortality. There are few effective approaches to SCA prevention for the general population. Identifying those at increased risk, and discovering novel therapeutic targets for arrhythmia prevention and treatment is of great public health importance. Hydrogen sulfide, H2S, is a toxic environmental pollutant that has recently emerged as an important physiological signaling molecule. H2S is one of three identified gasotransmitters (along with NO and CO) with significant biological roles in various tissues to maintain proper function. H2S is recognized as a cardioprotective substrate that preserves cardiomyocyte function and prevents toxicity. Most relevant to this application, H2S has electrophysiological significance in regulating L-type Ca2+, Na+ and ATP dependent K+ (KATP) channels that maintain a normal QT-period and reduce the prolonged QT period following ischemia reperfusion injury in various animal models. H2S also protects against ventricular tachyarrhythmia during cardiac hypertrophy and ischemia/reperfusion injury. Inhibition of the major enzyme responsible for H2S biosynthesis in cardiac tissue leads to reduced H2S levels in both cardiac tissue as well as circulating plasma, and results in cardiac injury. This research project will test the hypothesis that higher circulating H2S concentrations are associated with lower risk of SCA. Aim 1 will examine the risk associated with SCA and circulating H2S in plasma and RBC membranes in two large population-based studies of SCA. Aim 2 will test the role of H2S regulation in adult human cardiomyocyte dysfunction during hypoxic stress and for the first time, determine the genomic pathways associated with cardiac homeostasis of H2S to identify new pathways involved in the synthesis and especially metabolism of H2S under hypoxic stress. The two aims together will aid in developing new clinical strategies to combat SCA, improve risk stratification and identify novel H2S related drug targets for better treatment and prevention.

项目摘要 心脏骤停(SCA)仍然是一个主要的公共卫生问题，占高达 仅在美国，每年就有40万人死亡。在西方人群中，室颤是最常见的 SCA的电生理机制，而冠状动脉疾病(CAD)是最常见的基础 疾病。尽管最近在治疗和预防冠心病方面取得了进展，但SCA仍然是 导致死亡的主要原因。对于一般人来说，预防SCA的有效方法很少 人口。识别高危人群，发现心律失常的新治疗靶点 预防和治疗对公共卫生具有重要意义。 硫化氢，简称硫化氢，是一种有毒的环境污染物，近年来成为一种重要的环境污染物。 生理信号分子。硫化氢是公认的三种气体传递体之一(与NO和CO一起) 在各种组织中具有重要的生物学作用，以维持适当的功能。硫化氢被认为是一种 保护心脏的底物，保护心肌细胞功能并防止毒性。与此最相关的是 应用表明，硫化氢在调节L型钙、钠、三磷酸腺苷依赖中具有电生理意义 维持正常QT间期并缩短延长的QT间期的K+(KATP)通道 不同动物模型的缺血再灌注损伤。硫化氢还能预防室性快速性心律失常 在心肌肥厚和缺血/再灌流损伤过程中。抑制负责的主要酶 心脏组织中硫化氢的生物合成导致心脏组织和循环中的硫化氢水平降低 血浆，并导致心脏损伤。这项研究项目将检验更高循环的假设 硫化氢浓度与较低的SCA风险相关。目标1将检查与SCA相关的风险 和循环中的硫化氢在血浆和红细胞膜在两个大规模的人群为基础的SCA研究。目标2 将测试H_2S调节在成人低氧应激期间心肌细胞功能障碍中的作用 第一次，确定与硫化氢心脏内稳态相关的基因组途径，以确定新的 低氧胁迫下参与H_2S合成特别是代谢的途径。两个目的 共同努力将有助于开发新的临床策略，以对抗SCA，改善风险分层，并确定 新的硫化氢相关药物靶点，以更好地治疗和预防。

项目成果

METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.

METTL7A (TMT1A) 和 METTL7B (TMT1B) 负责肝脏中的烷基 S-硫醇甲基转移酶活性。

• DOI: 10.1124/dmd.123.001268
• 发表时间: 2023
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: Russell,DrakeA;Chau,MarvinK;Shi,Yuanyuan;Levasseur,IanN;Maldonato,BenjaminJ;Totah,RheemA
• 通讯作者: Totah,RheemA