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 突然心脏骤停（SCA）仍然是一个主要的公共卫生问题 仅在美国，每年40万人死亡。在西方人群中，心室纤颤是最常见的 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CAD方面取得了进步，但SCA仍然是其中之一 死亡的主要原因。一般的SCA预防有效方法很少 人口。确定风险增加的人，并发现心律不齐的新型治疗靶点 预防和治疗非常重要。 硫化氢H2S是一种有毒的环境污染物，最近成为重要的 生理信号分子。 H2S是三个已识别的燃气递质之一（以及NO和CO） 在各种组织中具有重要的生物学作用，以保持适当的功能。 H2S被认为是 保留心肌细胞功能并防止毒性的心脏保护基板。与此最相关 应用，H2S在调节L型Ca2+，Na+和ATP方面具有电生理学意义 K+（KATP）通道，该通道保持正常的QT-周期并减少延长的QT周期 各种动物模型中的缺血再灌注损伤。 H2还可以防止心室心律失常 在心脏肥大和缺血/再灌注损伤中。抑制主要酶 心脏组织中的H2S生物合成导致心脏组织中的H2S水平降低，循环 血浆，并导致心脏损伤。该研究项目将测试较高循环的假设 H2S浓度与SCA风险较低有关。 AIM 1将检查与SCA相关的风险 在两项基于人群的SCA研究中，血浆和RBC膜中的H2循环H2。目标2 将测试H2S调节在低氧应激期间成人人类心肌细胞功能障碍中的作用 第一次，确定与H2S心脏稳态相关的基因组途径以识别新的 在低氧应激下涉及H2S的合成，尤其是代谢的途径。两个目标 共同将有助于制定新的临床策略来打击SCA，改善风险分层并确定 新型H2S相关的药物靶标，可更好地治疗和预防。

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