Resolution of inflammation and atrial fibrillation

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.