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房颤患者中很常见。在心房肌细胞(CMS)中， NLRP3炎性小体激活和IL-1β分泌可诱发房颤。既然我们已经确立了 心脏NLRP3激活和IL-1β可导致房颤，我们将研究NLRP3的上游调节因子 可以通过操作来降低糖尿病患者房颤风险的炎症小刀。 我们已经发现，产生促炎分子的酶升高，炎症消退 患有糖尿病的人和小鼠的心房中分子减少。具体来说，我们发现增加了12- 脂氧合酶(12-LOX，由ALOX12编码)，是一种将花生四烯酸(AA)加工成蛋白质的酶. 人类和小鼠体内的炎性代谢物。在人类和小鼠身上，我们发现心脏前分解 脂质介体(SPM)是含有G蛋白偶联受体6(LGR6)的还原、富含亮氨酸的重复序列，编码 最近描述的SPMS受体LGR6)表达下调，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。 有待检验的假设：由于SPM可以减少NLRP3的激活，本应用程序探索DM- 相关的房颤风险可以通过减少炎性脂质介质增强SPM信号来减轻 产生(12-LOX抑制)，增强SPM信号(上调LGR6)，或减少SPM降解 (下调15-前列腺素DH)。 具体目标： 目的1：确定抑制心脏12-LOX上调是否会降低心房NLRP3的活性 糖尿病患者的房颤负荷。 特定目标2：确定心脏LGR6上调是否可以减少心房NLRP3的激活和 糖尿病患者的房颤负荷。 特定目标3：确定心脏15-PGDH下调是否可以减少心房NLRP3 糖尿病患者的激活与房颤负荷。 意义：这项应用探索了鼓励炎症消退的新治疗范例 预防糖尿病引起的房颤。在人类和小鼠身上进行平行实验将提供机械洞察力和 加强临床相关性。把重点放在预防而不是治疗上是新颖的，可以防止显著 与房颤发病相关的发病率。