Theranostics 2021; 11(6):2742-2754. doi:10.7150/thno.51183

Research Paper

Activation of EP4 receptor limits transition of acute to chronic heart failure in lipoxygenase deficient mice

Vasundhara Kain1, Kevin A. Ingle2, Namakkal S. Rajasekaran3, Ganesh V. Halade1✉

1. Division of Cardiovascular Sciences, Department of Medicine, University of South Florida.
2. Division of Nephrology, The University of Alabama at Birmingham, Alabama.
3. Department of Pathology, The University of Alabama at Birmingham, Alabama.

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Citation:
Kain V, Ingle KA, Rajasekaran NS, Halade GV. Activation of EP4 receptor limits transition of acute to chronic heart failure in lipoxygenase deficient mice. Theranostics 2021; 11(6):2742-2754. doi:10.7150/thno.51183. Available from https://www.thno.org/v11p2742.htm

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Abstract

Aim: Immune responsive 12/15 lipoxygenase (12/15LOX)-orchestrate biosynthesis of essential inflammation-resolution mediators during acute inflammatory response in post-myocardial infarction (MI). Lack of 12/15LOX dampens proinflammatory mediator 12-(S)-hydroxyeicosatetraenoic acid (12-(S)-HETE), improves post-MI survival, through the biosynthesis of endogenous mediators epoxyeicosatrienoic acids (EETs; cypoxins) to resolve post-MI inflammation. However, the mechanism that amplifies cypoxins-directed cardiac repair in acute heart failure (AHF) and chronic HF (CHF) remains of interest in MI-directed renal inflammation. Therefore, we determined the role of EETs in macrophage-specific receptor activation in facilitating cardiac repair in 12/15LOX deficient mice experiencing HF.

Methods and Results: Risk-free young adult (8 -12 week-old) male C57BL/6J wild-type mice (WT; n = 43) and 12/15LOX-/- mice (n = 31) were subjected to permanent coronary artery ligation and monitored at day (d)1, d5 (as acute HF), and d28 to d56 (8 weeks; chronic HF) post-surgery maintaining no-MI mice that served as d0 naïve controls. Left ventricle (LV) infarcted area of 12/15LOX-/- mice displayed an increase in expression of prostanoid receptor EP4 along with monocyte chemoattractant protein-1 CCL2 in AHF and CHF. The transcriptome analysis of isolated leukocytes (macrophages/neutrophils) from infarcted LV revealed a higher expression of EP4 on reparative macrophages expressing MRC-1 in 12/15LOX-/- mice. Deletion of 12/15LOX differentially modulated the miRNA levels, downregulating miR-23a-3p (~20 fold; p < 0.05) and upregulating miR-125a-5p (~160 fold; p < 0.05) in AHF which promoted polarization of the macrophages towards reparative phenotype. Furthermore, 12/15LOX deletion markedly attenuated renal inflammation with reduced levels of NGAL and KIM-1 and apoptotic markers in the kidney during CHF.

Conclusion: In risk-free mice during physiological cardiac repair, absence of 12/15LOX promoted reparative macrophages with marked activation of EP4 signaling thereby improving post-MI survival and limiting renal inflammation in acute and advanced HF. The future studies are warranted to advance the role of EETs in macrophage receptor biology.

Keywords: Inflammation, macrophages, leukocytes, resolution, cardiac remodeling, heart failure