Cardiovasc Res. 2026 Aug 17:cvag175. doi: 10.1093/cvr/cvag175. Online ahead of print.
ABSTRACT
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.
PMID:42605185 | DOI:10.1093/cvr/cvag175