Abstract: Current heart failure (HF) treatments are not effective in heart failure with preserved ejection fraction (HFpEF), despite the fact that 50% of all HF cases in the USA are HFpEF. Patients with HFpEF have high incidences of mortality, hospitalizations, and a poor quality of life. Thus, there is a critical need to find suitable therapeutic strategies for patients with HFpEF, based on pathophysiology. However, HFpEF pathophysiology is complex due to systemic comorbidities like obesity, diabetes, and hypertension. Systemic inflammation from such metabolic diseases a.k.a metabolic inflammation is key in driving the HFpEF pathogenesis. Chronic inflammation occurs due to the imbalance between proinflammation and resolution, including in HFpEF. Thus, we plan to develop suitable innovative therapies on strategies to improve the resolution of inflammation to curtail HFpEF progression. Resolution is an orchestrated process carried out by the actions of specialized pro-resolving mediators (SPMs) such as resolvins, lipoxins and maresins (secreted in inflammatory exudates). SPMs bind to their specific receptors to elicit tissue homeostasis by reducing further infiltration of leukocytes and increasing efferocytosis, i.e., clearing of cardiac apoptotic cells. Resolvin D1 (RvD1), one of the potent SPMs, acts via its receptor, formyl-peptide receptor-2 (FPR2) and decreases pro-inflammatory, pro-fibrotic gene expression and cytokines and promote efferocytosis. These effects are mediated via polarizing blood/bone marrow derived monocytes and splenic/myocardial macrophages from proinflammatory to pro- resolving phenotypes, that express FPR2. However, the effect of RVD1 in HFpEF, a big clinical issue with unresolved inflammation, has not been studied. The primary goal of our R21 proposal is to test the efficacy of RvD1 as a potential therapy for HFpEF driven by metabolic diseases. Thus, our proposal meets the goal of NIH’s Special Interest (NOSI-ES-20-018) notice: Promoting Fundamental and Applied Research in Inflammation Resolution. Mimicking all the features of human HFpEF in an animal model is challenging. However, db/db mice, a model of obesity mediated T2DM, recapitulate the major features of HFpEF; hence, we chose to employ db/db mice for the proposed studies. Our hypothesis is that RvD1 resolves systemic and cardiac inflammation by reprogramming monocytes/macrophages and thereby ameliorating metabolic stress associated with HFpEF. We propose two specific aims to test our hypothesis: 1) To determine the prophylactic effect of RvD1; and 2) To determine the therapeutic effect of RvD1. We will treat the mice systemically with RvD1 before (for prophylactic effects) and after (for therapeutic effects) onset of HFpEF. We will focus on RvD1 mediated increase in efferocytosis of dying cardiac cells i.e., coronary vascular endothelial cells (aim 1) and cardiomyocytes (aim 2) as its mechanism of action. The expected outcome of this project is to establish RvD1 a...