Cardiovasc Res. 2021 Mar 22:cvab111. doi: 10.1093/cvr/cvab111. Online ahead of print.
ABSTRACT
AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for endogenous medium/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress.
METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodeling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-days post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signaling and oxylipin synthesis as well as reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signaling-deficient Ffar4 R270H polymorphism correlated with eccentric remodeling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC.
CONCLUSIONS: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.
PMID:33752243 | DOI:10.1093/cvr/cvab111
