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.

房颤患者的全身炎症和氧化应激很常见。 我们已经确定，NLRP3 炎性体激活和 IL-1β 分泌可引发 AF。 心脏NLRP3激活和IL-1β可导致房颤，我们将研究心脏NLRP3的上游调节剂 可以操纵炎症小体来降低 DM 中的 AF 风险。 我们发现产生促炎分子的酶会加剧炎症并解决 具体来说，我们发现患有 DM 的人类和小鼠心房中的分子减少了，12- 增加了。 脂氧合酶（12-LOX，由 ALOX12 编码），一种将花生四烯酸 (AA) 加工成亲- 在人类和小鼠中，我们发现心脏促消退。 脂质介质 (SPM) 减少，富含亮氨酸的重复序列含有 G 蛋白偶联受体 6（LGR6，编码 最近描述的 SPM 受体 LGR6 被下调，并且 15-羟基前列腺素 脱氢酶（15-PGDH；由 HPGD 编码）是一种使 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 NLRP3 激活，本申请探讨了 DM 是否 通过减少炎症脂质介质来增强 SPM 信号传导，可以减轻相关的 AF 风险 产生（12-LOX 抑制）、增强 SPM 信号传导（上调 LGR6）或减少 SPM 降解 （15-PGDH 下调）。 具体目标： 目标 1：确定抑制心脏 12-LOX 上调是否可以减少心房 NLRP3 激活 和 DM 中的 AF 负担。 具体目标 2：确定心脏 LGR6 的上调是否可以减少心房 NLRP3 的激活和 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 NLRP3 DM 中的激活和 AF 负担。 意义：该应用探索了促进炎症消退的新治疗范例 在人类和小鼠中进行平行实验将有助于预防 DM 诱发的 AF。 加强临床相关性是新颖的，可以预防重大疾病的发生。 与 AF 发病相关的发病率。