Heart failure (HF) after myocardial infarction (MI) is a significant cause of morbidity and mortality. Identifying the events that limit adverse remodeling of the left ventricle (LV) post-MI will provide therapeutic targets to prevent, slow, or reverse progression to HF. MI initiates the ?get-in? signal for immune cells including neutrophils, which if unchecked causes uncontrolled pro-inflammatory activity that in turn leads to HF. Our post-MI studies suggest that spleen coordinates the resolution of inflammation through a cardiosplenic pathway. These findings reveal an urgent clinical need to establish the mechanisms by which the spleen mediates this resolution. It was previously believed that resolution of inflammation is an inert process, but emerging data confirms that this is an active process managed by specialized pro-resolving molecules (SPMs) derived from omega-3 and omega-6 fatty acids. Our R00 study in an HF setting confirms that the spleen produces various SPMs, including lipoxins, resolvins, and maresins post-MI, and exogenous treatment with resolvin D1 (RvD1) clears inflammation in a cardiosplenic manner. We discovered that exogenous RvD1 clears neutrophils and resolves inflammation by activating neutrophil-expressed formyl peptide receptor 2 (FPR2) in the left ventricle and spleen post-MI. This proof-of-concept study using RvD1 in mice provides the foundation for investigation of the resolvins-mediated mechanism of action in chronic HF. These data implicate activation of neutrophil receptors in promoting the ?get-out? signal for effective resolution of inflammation post-MI. To achieve our overall goal of activating immune cells in the healing phase after MI, we propose to establish: 1) the role of RvD1 in resolution of inflammation in chronic HF; 2) whether activation of this ?get-out? signal is enough to resolve post-MI inflammation in HF using FPR2 knockout mice to abolish RvD1 action and resultant HF; and 3) the novel mechanism of action of RvD1 on neutrophil-expressed CD10 in the cardiosplenic axis, as suggested by our innovative in silico computational modeling. Our initial studies in mice have confirmed the role of RvD1 in acute HF. Now, we propose a mechanistic study to extend in silico, ex vivo, and acute HF (day 5) outcomes to chronic HF (day 28), which is key for translation and to indicate survival benefit to HF patients. Non-immunosuppressive pro-resolving therapy is an unmet medical need and has the potential to be the first ever effective therapy to control chronic inflammation and delay HF in a cardiosplenic manner. These studies will identify immune cell-specific novel targets for lipid mediators in a ligand-receptor-specific pathway, rather than antibody or cytokine-specific inhibition, which will likely enhance therapeutic applications in patients with HF within the next 5-6 years.

Public Health Relevance

Heart failure (HF) is highly prevalent after heart attack, and associates with a poor prognosis and high economic burden. According to the 2013 statistics of the American Heart Association, more than 5 million American adults have HF. In this project, we will test in mice with HF a new specialized bioactive molecule that clears overactive immune cell populations after heart attack to resolve the inflammation and reduce heart damage characteristic of this disease. Our approach is highly promising based on our preliminary work, and may have considerable clinical implications for patients with HF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132989-04
Application #
9685929
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2016-07-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Halade, Ganesh V; Black, Laurence M; Verma, Mahendra Kumar (2018) Paradigm shift - Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery. Biotechnol Adv 36:935-953
Halade, Ganesh V; Norris, Paul C; Kain, Vasundhara et al. (2018) Splenic leukocytes define the resolution of inflammation in heart failure. Sci Signal 11:
Kain, Vasundhara; Ingle, Kevin A; Kabarowski, Janusz et al. (2018) Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction. J Mol Cell Cardiol 118:70-80
Halade, Ganesh V; Kain, Vasundhara; Ingle, Kevin A (2018) Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology. Am J Physiol Heart Circ Physiol 314:H255-H267
Kain, Vasundhara; Ingle, Kevin A; Kachman, Maureen et al. (2018) Excess ?-6 fatty acids influx in aging drives metabolic dysregulation, electrocardiographic alterations, and low-grade chronic inflammation. Am J Physiol Heart Circ Physiol 314:H160-H169
Halade, Ganesh V; Dorbane, Anela; Ingle, Kevin A et al. (2018) Comprehensive targeted and non-targeted lipidomics analyses in failing and non-failing heart. Anal Bioanal Chem 410:1965-1976
Halade, Ganesh V; Kain, Vasundhara; Serhan, Charles N (2018) Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure. FASEB J 32:3717-3729
Tourki, Bochra; Halade, Ganesh (2017) Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. FASEB J 31:4226-4239
Kain, Vasundhara; Halade, Ganesh V (2017) Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy. Front Cardiovasc Med 4:31
Halade, Ganesh V; Kain, Vasundhara (2017) Obesity and Cardiometabolic Defects in Heart Failure Pathology. Compr Physiol 7:1463-1477

Showing the most recent 10 out of 11 publications