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Contribution of PPARα/β/γ, AP-1, importin-α3, and RXRα to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against hypotension, tachycardia, and inflammation in a rat model of septic shock

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Abstract

Objectives

We have previously demonstrated that downregulation of the MyD88/TAK1-dependent signaling pathway associated with increased CYP4A1 expression and 20-HETE formation participates in the protective effect of N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), a 20-HETE mimetic, against vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The aim of this study was to determine whether increased renal and cardiovascular expression of PPARα/β/γ and RXRα associated with decreased expression and/or activity of AP-1 and importin-α3 participates in the protective effect of 5,14-HEDGE in response to systemic administration of lipopolysaccharide (LPS).

Methods

Conscious male Wistar rats received saline (4 ml/kg) or LPS (10 mg/kg) at time 0. Blood pressure and heart rate were measured using a tail-cuff device. Separate groups of LPS-treated rats were given 5,14-HEDGE (30 mg/kg) 1 h after injection of saline or LPS. The rats were killed 4 h after saline or LPS administration and the kidney, heart, thoracic aorta, and superior mesenteric artery were collected for measurement of protein expression.

Results

Blood pressure fell by 33 mmHg and heart rate rose by 72 beats/min at 4 h after LPS administration. In LPS-treated rats, tissue protein expressions of cytosolic/nuclear PPARα/β/γ and nuclear RXRα, in addition to nuclear translocation of PPARα/β/γ proteins, were decreased, while cytosolic/nuclear AP-1 subunit c-jun/phosphorylated c-jun and importin-α3 protein expression as well as their nuclear translocation were increased. The LPS-induced changes were prevented by 5,14-HEDGE.

Conclusions

The results suggest that an increase in the expression of PPARα/β/γ and RXRα as well as a decrease in AP-1 and importin-α3 expression/activity participates in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation during endotoxemia and thus have a beneficial effect in septic shock treatment.

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Abbreviations

15d-PGJ2 :

15-Deoxy-Δ12,14-prostaglandin J2

20-HETE:

20-Hydroxyeicosatetraenoic acid

5,14-HEDGE:

N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine

AP:

Activator protein

BSA:

Bovine serum albumin

CD:

Cluster of differentiation

COX:

Cyclooxygenase

Crm:

Chromosome region maintenance

CYP:

Cyctochrome P450

DNA:

Deoxyribonucleic acid

ERK:

Extracellular signal-regulated kinase

HR:

Heart rate

Ig:

Immunoglobulin

IKK:

IκB kinase

IκB:

Inhibitor of κB

IL:

Interleukin

i.p.:

Intraperitoneally

IL:

Interleukin

IRAK:

Interleukin-1 receptor-associated kinase

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

MAP:

Mean arterial pressure

MAPK:

Mitogen-activated protein kinase

MD:

Myeloid differentiation protein

MEK:

Mitogen-activated protein kinase kinase

MKK:

Mitogen-activated protein kinase kinase

miRNA:

Microribonucleic acid

MyD88:

Myeloid differentiation factor 88

NADPH:

Nicotinamide adenine dinucleotide phosphate

NES:

Nuclear export signals

NF-κB:

Nuclear factor-κB

NFAT:

Nuclear factor of activated T cells

NLS:

Nuclear localization signals

NO:

Nitric oxide

PG:

Prostaglandin

PPAR:

Peroxisome proliferator-activated receptor

PPREs:

Peroxisome proliferator-activated receptor response elements

RXR:

Retinoid X receptor

s.c.:

Subcutaneously

SEM:

Standard error of means

STAT:

Signal transducer and activator of transcription

TAK:

Transforming growth factor-activated kinase

TIRAP:

Toll-interleukin-1 receptor domain containing adaptor protein

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TRAF:

TNF receptor-associated factor

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Acknowledgments

Financial support was provided by grants from Mersin University (BAP-SBE FB [SPS] 2014-3 YL, the Robert A. Welch Foundation (I-0011), and NIH (HL111392). The results of this study were included in the Master’s Thesis of Pharm. M.S. Sefika Pinar Senol.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey

    Sefika Pinar Senol, Meryem Temiz, Demet Sinem Guden, Pelin Cecen, Ayse Nihal Sari, Seyhan Sahan-Firat & Bahar Tunctan

  2. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    John R. Falck & Rambabu Dakarapu

  3. Department of Pharmacology, College of Medicine, Center for Health Sciences, University of Tennessee, Memphis, TN, USA

    Kafait U. Malik

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Senol, S.P., Temiz, M., Guden, D.S. et al. Contribution of PPARα/β/γ, AP-1, importin-α3, and RXRα to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against hypotension, tachycardia, and inflammation in a rat model of septic shock. Inflamm. Res. 65, 367–387 (2016). https://doi.org/10.1007/s00011-016-0922-5

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