PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS

Victor Samokhvalov, Jelle Vriend, Kristi L. Jamieson, Maria K. Akhnokh, Rajkumar Manne, J R Falck, John M. Seubert

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article number242
JournalFrontiers in Pharmacology
Volume5
Issue numberNOV
DOIs
StatePublished - 2014

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Peroxisome Proliferator-Activated Receptors
Cardiac Myocytes
Lipopolysaccharides
Arachidonic Acids
Epoxide Hydrolases
Cellular Structures
Endotoxins
Caspase 3
Cell Survival
Cell Death
Anti-Inflammatory Agents
Antioxidants
Pharmacology
Inflammation
Acids
14,15-epoxy-5,8,11-eicosatrienoic acid

Keywords

  • Cardiac cells
  • Epoxyeicosatrienoic acid
  • Inflammation
  • LPS
  • PPARγ

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS. / Samokhvalov, Victor; Vriend, Jelle; Jamieson, Kristi L.; Akhnokh, Maria K.; Manne, Rajkumar; Falck, J R; Seubert, John M.

In: Frontiers in Pharmacology, Vol. 5, No. NOV, 242, 2014.

Research output: Contribution to journalArticle

Samokhvalov, Victor ; Vriend, Jelle ; Jamieson, Kristi L. ; Akhnokh, Maria K. ; Manne, Rajkumar ; Falck, J R ; Seubert, John M. / PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS. In: Frontiers in Pharmacology. 2014 ; Vol. 5, No. NOV.
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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.",
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AU - Samokhvalov, Victor

AU - Vriend, Jelle

AU - Jamieson, Kristi L.

AU - Akhnokh, Maria K.

AU - Manne, Rajkumar

AU - Falck, J R

AU - Seubert, John M.

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