Archives
br The potential of EPA
The potential of EPA-Ffar4 signaling as a novel intervention for HFpEF
Conclusions and future directions
Optimization of ω3-PUFA/EPA-therapy based upon titration to achieve therapeutic levels: A pressing clinical challenge is to continue to define the benefit of ω3-PUFA/EPA-therapy. Recent analyses suggest that current clinical failures might be attributable to failure to achieve a therapeutic concentration of ω3-PUFAs [43]. This is the case with triglycerides where efficacy is a function of both baseline ω3-PUFAs and response to treatment [121]. This suggests that ω3-PUFA/EPA-therapy should be dictated by targeting therapeutic levels of ω3-PUFAs in patients rather than dictated by dosage given. However, most trials are performed with a fixed dose (intention-to-treat study design), leading to variability in patient blood levels of ω3-PUFA, with most failing to achieve a therapeutic level.
Understanding the variability in basal cardiac fatty Cy5 maleimide (non-sulfonated) profiles and how this impacts basal Ffar4 signaling: Ffar4 binds to and is activated by numerous long-chain FA [63], [67], and at this time it is unclear how basal activity of Ffar4 in cardiac fibroblasts, or any other cell expressing Ffar4, is affected by variations in tissue-specific and/or blood FA composition.
How a shift away from thinking of free fatty acids as an energy source to how their effects on Ffar4 activity in cardiac fibroblasts and myocytes may be a promising future direction of research and therapeutics for HF.
Developing reliable small animal models of HFpEF: The lack of an animal model for HFpEF is one of the most significant challenges to understanding and developing novel therapies for HFpEF [94]. Several small animal hypertensive models have been proposed that resemble aspects of HFpEF including Dahl salt-sensitive rats, DOCA mice, angiotensin II infusion, spontaneously hypertensive rat, and TAC, but all have limitations (Review: [122]). At this time, there is no small animal HF model that fully recapitulates human HFpEF.
Development of novel Ffar4 ligands and testing in preclinical models of HFpEF and human HFpEF: Although there is research into developing novel Ffar4 ligands (Review: [72]), no current work is directed toward developing Ffar4 ligands specifically for HF.
Disclosures
Acknowledgements
Introduction
G protein-coupled receptors (GPCRs) represent the largest and most diverse family of cell surface receptors and are known to regulate a variety of physiological processes. GPCRs also represent the largest family of drugged proteins, with some estimates suggesting that roughly 40% of marketed drugs target a member of the superfamily. Sequencing of the human genome revealed almost 900 distinct GPCR-encoding genes, with almost half of these classified as chemosensory receptors that transmit signals in response to olfaction or gustation, while approximately one-third have been characterized as ‘deorphanized’ receptors that bind a cognate endogenous ligand [1]. Currently, less than 100 GPCRs remain classified as ‘orphan’ receptors, lacking positive identification of an associated endogenous ligand [1]. Bioinformatic mining coupled with molecular biology based approaches in the early 2000s revealed a subfamily of orphan GPCRs, including GPR40, GPR43, GPR41, and GPR120, which were subsequently shown to recognize and be agonized by endogenous and dietary free fatty acids (FFA) [2], [3]. As a consequence of their deorphanization, these free-fatty acid receptors have recently been renamed by the International Union of Basic and Clinical Pharmacology as FFA1, FFA2, FFA3, and FFA4, respectively [4]. FFA2 and FFA3 recognize and are agonized by short-chain fatty acids such as acetate, propionate, and butyrate, which are the primary metabolic byproducts of anaerobic fermentation by intestinal microflora [5]. Meanwhile, though FFA1 and FFA4 share low sequence homology, they are both activated by medium and long-chain fatty acids, including the family of omega-3 (n-3) polyunsaturated fatty acids (PUFA), typified by α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) [4].