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Published on: June 3, 2018
Free fatty acid receptor 4 in cardiac myocytes ameliorates ischemic cardiomyopathy
Michael J Zhang1,2,3, Sara J Puccini1, Sergey Karachenets1
1Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN.
Aims:
Free fatty acid receptor 4 (Ffar4) is a receptor for long-chain fatty acids that attenuates heart failure driven by increased afterload. Recent findings suggest that Ffar4 prevents ischemic injury in brain, liver, and kidney, and therefore, we hypothesized that Ffar4 would attenuate cardiac ischemic injury.
Methods And Results:
Using a mouse model of ischemia-reperfusion (I/R), we found in mice with systemic deletion of Ffar4 (Ffar4KO), loss of Ffar4 impaired the recovery of left ventricular systolic function post-I/R with no effect on initial infarct size. To identify potential mechanistic explanations for the cardioprotective effects of Ffar4, we performed bulk RNAseq to compare the transcriptomes from wild-type (WT) and Ffar4KO infarcted myocardium 3-days post-I/R. The transcriptome analysis identified the downregulation of several metabolic pathways suggesting impaired mitochondrial function in the infarcted Ffar4KO myocardium. Mechanistically, basal mitochondrial function and morphology were impaired in cardiac myocytes from Ffar4KO mice corroborating the results of the transcriptome analysis. Interestingly, phosphodiesterase 6c (Pde6c), which degrades cGMP, was the most upregulated gene in the Ffar4KO heart. Further, the soluble guanylyl cyclase stimulator, vericiguat, failed to increase cGMP in Ffar4KO cardiac myocytes, suggesting increased phosphodiesterase activity. Finally, cardiac myocyte-specific overexpression of Ffar4 in vivo and activation of Ffar4 in cardiac myocytes in vitro attenuated ischemic/hypoxic injury respectively.
Conclusions:
Our results define a novel protective role for Ffar4 in cardiac myocytes to attenuate systolic dysfunction and prevent ischemic cardiomyopathy post I/R by preserving mitochondrial function and activating cGMP signaling.
Insights
Free fatty acid receptor 4 (Ffar4) protects the heart from ischemic injury by preserving mitochondrial function and activating cGMP signaling, thus preventing systolic dysfunction and ischemic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Receptor Pharmacology
Background:
- Free fatty acid receptor 4 (Ffar4) is implicated in attenuating heart failure and preventing ischemic injury in various organs.
- Previous research suggests Ffar4's protective role in non-cardiac tissues, prompting investigation into its cardiac functions.
Purpose of the Study:
- To investigate the role of Ffar4 in attenuating cardiac ischemic injury.
- To elucidate the underlying mechanisms by which Ffar4 exerts cardioprotection.
Main Methods:
- Utilized a mouse model of ischemia-reperfusion (I/R) injury.
- Performed bulk RNA sequencing (RNAseq) on wild-type (WT) and Ffar4 knockout (Ffar4KO) infarcted myocardium.
- Assessed mitochondrial function and morphology in cardiac myocytes.
- Investigated cGMP signaling pathways.
Main Results:
- Loss of Ffar4 impaired left ventricular systolic function recovery post-I/R but did not affect initial infarct size.
- Transcriptome analysis revealed downregulated metabolic pathways and impaired mitochondrial function in Ffar4KO hearts.
- Upregulation of phosphodiesterase 6c (Pde6c) and impaired cGMP response were observed in Ffar4KO cardiac myocytes.
- Cardiac myocyte-specific Ffar4 overexpression attenuated ischemic injury.
Conclusions:
- Ffar4 plays a novel protective role in cardiac myocytes against ischemia-reperfusion injury.
- Ffar4 preserves mitochondrial function and activates cGMP signaling to prevent systolic dysfunction and ischemic cardiomyopathy.
- Targeting Ffar4 may offer a therapeutic strategy for ischemic heart disease.
