Ffar4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome
2023-02
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Ffar4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome
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2023-02
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Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex clinicalsyndrome, but a predominant subset of HFpEF patients has metabolic syndrome
(MetS). Mechanistically, systemic, non-resolving inflammation associated with MetS
might drive HFpEF remodeling. Free fatty acid receptor 4 (FFAR4) is a GPCR for
long-chain fatty acids that attenuates metabolic dysfunction and resolves
inflammation. Therefore, we hypothesized that FFAR4 would attenuate remodeling in
HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with
systemic deletion of FFAR4 (FFAR4KO) were fed a high-fat/high-sucrose diet with LNAME
in their water to induce HFpEF-MetS. In male FFAR4KO mice, this HFpEFMetS
diet induced similar metabolic deficits, but worsened diastolic function and
microvascular rarefaction relative to wild-type (WT) mice. Conversely, in female
FFAR4KO mice, the diet produced greater obesity but no worsened ventricular
remodeling relative to WT mice. In FFAR4KO males, MetS altered the balance of
inflammatory oxylipins systemically in HDL and in the heart, decreasing the
eicosapentaenoic acid-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic
acid (18-HEPE), while increasing the arachadonic acid-derived, proinflammatory
oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-
HEPE ratio reflected a more proinflammatory state both systemically and in the heart
in male FFAR4KO mice, and was associated with increased macrophage numbers in
the heart, which in turn correlated with worsened ventricular remodeling. In summary,
our data suggest that FFAR4 controls the proinflammatory/pro-resolving oxylipin
balance systemically and in the heart to resolve inflammation and attenuate HFpEF
remodeling.
Description
University of Minnesota Ph.D. dissertation. 2023. Major: Integrative Biology and Physiology. Advisors: Timothy O'Connell, Catherine Kotz. 1 computer file (PDF); 120 pages.
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Zhang, Naixin. (2023). Ffar4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/257063.
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