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

Abstract

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.

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock

“…Consistent with our previous findings, 1,4,32–36 injection of LPS into rats also resulted in a progressive reduction in MAP and a rise in HR over the 4-hour course of the experiment (Table 1). MAP reduced by 33 mm Hg and HR increased by 102 beats/min (bpm) 4 hours after LPS injection into the rats ( P < 0.05).…”

“…Furthermore, 6,15-HEDGE, a competitive antagonist of the vasoconstrictor effects of 20-HETE, reversed the effects of 5,14-HEDGE on the LPS-induced changes. According to the results of our previous studies on the septic shock model induced by LPS injection, 1,4,32,33,35,36 we concluded that 20-HETE mimetics such as 5,14-HEDGE may be useful in preventing events leading to vascular hyporeactivity to vasoconstrictors, vascular dysfunction, hypotension, tachycardia, inflammation, and mortality accompanied mainly by the (1) activation of the myeloid differentiation factor (MyD) 88/ transforming growth factor-activated kinase (TAK) 1/ inhibitor of kB kinase b/inhibitor of kB-a/NF-kB, (2) MyD88/TAK1MAPK kinase 1/extracellular signal-regulated kinase 1/2/activator protein 1, and (3) peroxisome proliferator-activated receptor-a, -b, and g/retinoid X receptor a signaling pathways triggered by LPS. We also demonstrated that the decreased generation of proinflammatory cytokines (ie, interleukin-1b, 28, and tumor necrosis factor [TNF] a) and vasodilator molecules (ie, NO, prostaglandin I 2 [PGI 2 ], and epoxyeicosatrienoic acids, EETs) in addition to increased formation of vasoconstrictor eicosanoids (ie, 20-HETE) mediates the effects of 5,14-HEDGE on the LPS-induced changes.…”

“…injection of saline (4 mL/kg]) or LPS (Escherichia coli LPS, O111:B4; L4130; Sigma Chemical Co, St. Louis, MO) (10 mg/kg; 4 mL/kg). 1,4,32,33,35,36 5,14-HEDGE and 6,15-HEDGE were kindly provided by J. R. Falck in the Department of Biochemistry University of Texas Southwestern Medical Center, Dallas, TX. A tail-cuff device (MAY 9610 Indirect Blood Pressure Recorder System, Commat Ltd, Ankara, Turkey) was used for the measurement of mean arterial pressure (MAP) and heart rate (HR) values of the animals at times 0 and 1, 2, 3, and 4 hours.…”

PPAR‐γ Activation Prevents Septic Cardiac Dysfunction via Inhibition of Apoptosis and Necroptosis

“…In recent decades, peroxisome proliferator-activated receptor gamma (PPAR- γ ), a ligand-activated transcription factor that is involved in cell proliferation, lipid metabolism, and inflammation [ 11 ], emerges as a regulator of inflammatory responses [ 12 ]. Increase or activation of PPAR- γ has been shown to improve survival in animal models of sepsis [ 13 , 14 ]. In the cecal ligation and puncture (CLP) model of sepsis, PPAR- γ agonist ameliorates systemic inflammation by decreasing plasma levels of TNF- α and IL-6 via inhibition of nuclear factor kappa B (NF- κ B) [ 15 , 16 ].…”

The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis

“…The endotoxemia model, therefore, represents a relevant physiological model of sepsis. In a rat model of LPS-induced septic shock, tissue protein expression (renal and cardiac) of cytosolic and nuclear PPARα, PPARδ and PPARγ and nuclear translocation of these proteins were decreased with LPS [50]. In a rodent model of septic shock, early administration of a selective RXR agonist (bexarotene) was shown to prevent LPS-induced decrease in mean arterial pressure, as well as LPS-induced decreases in tissue PPARα/δ/γ-RXRα heterodimer formation [51].…”