Resolution of inflammation and atrial fibrillation

炎症和心房颤动的解决

• 批准号: 10679718
• 负责人: SAMUEL C DUDLEY
• 金额: $ 73.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679718
• 关键词: Applied Research; Arachidonate 12-Lipoxygenase; Arachidonic Acids; Arrhythmia; Atrial Fibrillation; CCL2 gene; Cardiac; Cardiac Myocytes; Diabetes Mellitus; Down-Regulation; Enzymes; Equilibrium; Fatty Acids; GPR6 gene; Heart; Heart Atrium; Human; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; LOX gene; Leucine-Rich Repeat; Lipids; Macrophage; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Mus; Obesity; Oxidative Stress; Oxidoreductase; Patients; Prevention; Process; Production; Resolution; Risk; Risk Factors; Signal Transduction; Testing; Transmembrane Domain; Up-Regulation; Writing; clinically relevant; diabetic; experimental study; fundamental research; human tissue; improved; insight; knock-down; lipid mediator; migration; mouse model; novel; prevent; receptor; response; systemic inflammatory response

Systemic inflammation and oxidative stress are common in patients with AF. In atrial cardiomyocytes (CMs), AF can be precipitated by NLRP3 inflammasome activation and IL-1β secretion. Since we have established cardiac NLRP3 activation and IL-1β can lead to AF, we will study upstream modulators of the cardiac NLRP3 inflammasome that can be manipulated to reduce AF risk in DM. We have found that enzymes producing pro-inflammatory molecules are elevated and inflammation resolving molecules are reduced in atria from humans and mice with DM. Specifically, we have found increased 12- lipoxygenase (12-LOX, encoded by ALOX12), an enzyme that processes arachidonic acid (AA) to pro- inflammatory metabolites in humans and mice. In humans and mice, we have found that cardiac pro-resolving lipid mediators (SPMs) are reduced, leucine-rich repeat containing G protein-coupled receptor 6 (LGR6, encoded by LGR6), a recently described receptor of SPMs, is downregulated, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH; encoded by HPGD), an enzyme in the inactivation of SPMs, is increased in DM atria. Hypotheses to be tested: Since SPMs can reduce NLRP3 activation, this application explores whether DM- associated AF risk can be mitigated by enhancing SPM signaling by reducing inflammatory lipid mediator production (12-LOX inhibition), enhancing SPM signaling (upregulation of LGR6), or reducing SPM degradation (downregulating of 15-PGDH). Specific aims: Aim 1: Determine whether inhibition of cardiac 12-LOX upregulation can reduce atrial NLRP3 activation and AF burden in DM. Specific Aim 2: Determine whether upregulation of cardiac LGR6 can reduce atrial NLRP3 activation and AF burden in DM. Specific Aim 3: Determine whether downregulation of cardiac 15-PGDH can reduce atrial NLRP3 activation and AF burden in DM. Significance: This application explores new treatment paradigms of encouraging inflammation resolution to prevent DM-induced AF. Using parallel experiments in humans and mice will provide mechanistic insights and strengthen clinical relevance. A focus on prevention rather than treatment is novel and could prevent significant morbidity associated with AF onset.

全身炎症和氧化应激在AF患者中很常见。在心房心肌细胞（CM）中， AF可通过NLRP 3炎性体活化和IL-1β分泌来沉淀。自从我们建立了 心脏NLRP 3激活和IL-1β可导致AF，我们将研究心脏NLRP 3的上游调节剂 炎性小体，可以操纵，以减少糖尿病房颤的风险。 我们发现，产生促炎分子的酶升高，炎症消退 分子在患有DM的人和小鼠的心房中减少。具体来说，我们发现增加了12- 脂氧合酶（12-LOX，由ALOX 12编码），一种将花生四烯酸（AA）加工成前- 人类和小鼠的炎症代谢物。在人类和小鼠中，我们发现心脏促消退 脂质介质（SPM）减少，富含亮氨酸重复的G蛋白偶联受体6（LGR 6，编码 由LGR 6），一种最近描述的SPM受体，被下调，并且15-羟基前列腺素 脱氢酶（15-PGDH;由HPGD编码），一种SPM失活的酶，在DM心房中增加。 待检验的假设：由于SPM可以减少NLRP 3激活，因此本申请探索了DM-1是否可以降低NLRP 3激活。 通过减少炎症脂质介质， 产生（12-LOX抑制）、增强SPM信号传导（上调LGR 6）或减少SPM降解 （下调15-PGDH）。 具体目标： 目的1：确定抑制心脏12-LOX上调是否可以减少心房NLRP 3激活 和DM中的AF负担。 具体目标2：确定心脏LGR 6的上调是否可以减少心房NLRP 3激活， DM中的AF负担。 具体目标3：确定心脏15-PGDH的下调是否可以降低心房NLRP 3 DM中的激活和AF负担。 意义：该应用探索了鼓励炎症消退的新治疗模式， 预防DM诱导的AF。在人类和小鼠中使用平行实验将提供机制见解， 加强临床针对性。注重预防而不是治疗是一种新的做法， 与AF发作相关的发病率。