title: PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS.
abstract: Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Epoxyeicosatrienoic acids (EETs) are biologically active metabolites of arachidonic acids capable of activating protective cellular pathways in response to stress stimuli. EETs evoke a plethora of pathways limiting impairments of cellular structures, reducing cell death, and promoting anti-inflammatory reactions in various cell types. Considering EETs are capable of producing various biological protective effects, we hypothesized that EETs would protect rat neonatal cardiomyocytes (NCM) against LPS-induced cytotoxicity. In this study, we used a dual-acting, synthetic analog of EETs, UA-8 [13-(3-propylureido)tridec-8-enoic acid], possessing both EET-mimetic and soluble epoxide hydrolase selective inhibitory properties and 14,15-EET as a model of canonical EET molecules. We found that both UA-8 and 14,15-EET significantly improved cell viability and mitochondrial function of cardiomyocytes exposed to LPS. Furthermore, treatment with UA-8 or 14,15-EET resulted in significant attenuation of LPS-triggered pro-inflammatory response, caspase-3 activation and reduction in the total antioxidant capacity in cardiomyocytes. Importantly, EET-mediated effects were significantly reduced by pharmacological inhibition of peroxisome proliferator-activated receptors γ (PPARγ) suggesting that PPARγ signaling was required for EETs exerted protective effects. Data presented in the current study demonstrate that activation of PPARγ signaling plays a crucial role in EET-mediated protection against LPS-cytotoxicity in cardiomyocytes.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta Edmonton, AB, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Samokhvalov
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta Edmonton, AB, Canada ; Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Vriend
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta Edmonton, AB, Canada.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Jamieson
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta Edmonton, AB, Canada.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Akhnokh
authors.affiliation: Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Manne
authors.affiliation: Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta Edmonton, AB, Canada ; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta Edmonton, AB, Canada.
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
keywords: LPS; PPARγ; cardiac cells; epoxyeicosatrienoic acid; inflammation