PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

Ji, Yuanyuan; Liu, Juntian; Wang, Zhidong; Liu, Na; Gou, Wei

doi:10.1038/labinvest.2009.45

Cited by 80 publications

(52 citation statements)

References 45 publications

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“…The PPARγ ligandmediated suppression of AT1R expression was also demonstrated in Ang II-infused rats [8,9]. Moreover, PPARγ ligands have been shown to suppress Ang IIinduced phosphatidylinositol 3-kinase and MAP kinase [9], and ameliorate Ang II-mediated inflammatory responses by interfering with the Toll-like receptor 4-dependent signaling pathway [10]. Therefore, PPARγ not only down-regulates AT1R expression, but also inhibits Ang II-mediated signaling pathways, which may result in the suppression of the RAS (Fig.…”

Section: Effects Of Pparγ On Hypertensionmentioning

confidence: 89%

Effects of PPAR.GAMMA. on hypertension, atherosclerosis, and chronic kidney disease

et al. 2010

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Abstract. Peroxisome proliferator-activated receptor (PPAR) γ is a nuclear hormone receptor that is trans-activated by its ligands including insulin-sensitizing thiazolidinediones. PPARγ has recently been reported to demonstrate pleiotropic beneficial effects in the vasculatures, independent of its blood glucose-lowering effects. Firstly, PPARγ ligands have been shown to lower blood pressure in both animals and human. The effect may possibly be mediated via the PPARγ-mediated inhibition of the angiotensin (Ang) II type 1 receptor expression as well as Ang II-mediated signaling pathways, which may result in the suppression of the renin-angiotensin system (RAS). Secondly, the progression of atherosclerosis was also prevented by PPARγ ligands in both animals and human. In addition to the PPARγ-mediated suppression of the RAS and the thromboxane A 2 system, protective effects of PPARγ ligands on endothelial function may also be involved. Thirdly, reno-protective effects of PPARγ ligands, especially on reducing urinary albumin, have been observed in both animals and human not only in diabetic nephropathy but also in non-diabetic renal diseases. The reno-protective effects may be mediated, at least in part, via the PPARγ ligand-induced blood pressure-lowering effects, protective effects on endothelial function, and vasodilating effects on the glomerular efferent arterioles. Additionally, anti-cancer effects of PPARγ ligands have recently been reported. Taken together, usefulness and effectiveness of PPARγ ligands on lifestyle related diseases will be increasingly appreciated.

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Section: Effects Of Pparγ On Hypertensionmentioning

confidence: 89%

Effects of PPAR.GAMMA. on hypertension, atherosclerosis, and chronic kidney disease

et al. 2010

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“…The reconstitution system we have established, allows a direct and extensive comparison of the responses of TLR4 to LPS. Numerous studies have indicated ameliorating properties of PPARc in LPS-induced inflammatory conditions in a variety of cells (Zhang et al 2010 andJung et al 2012;Ji et al 2009 andZhao et al 2011;Wang et al 2011;Necela et al 2008;Yin et al 2013Yin et al , 2014. To clarify whether anti-inflammatory effects of PPARc are mediated via TLR4 receptor inhibition, we implemented such reporter cell.…”

Section: Discussionmentioning

confidence: 99%

“…Peroxisome proliferator-activated receptor-gamma (PPARc) is a ligand-activated transcription factor with numerous biological effects. It also exerts a potential anti-inflammatory effect by suppressing TLR4-mediated inflammation Jung et al 2012;Ji et al 2011;Zhao et al 2011;Wang et al 2011;Zhang et al 2010;Ji et al 2009;Necela et al 2008;Yin et al 2013Yin et al , 2014.…”

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confidence: 99%

PPARγ ameliorated LPS induced inflammation of HEK cell line expressing both human Toll-like receptor 4 (TLR4) and MD2

et al. 2015

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TLR4 is transmembrane pattern-recognition receptor that initiates signals in response to diverse pathogen-associated molecular patterns especially LPS. Recently, there have been an increasing number of studies about the role of TLRs in the pathogenesis of several disorders as well as the therapeutic potential of TLR intervention in such diseases. Peroxisome proliferator-activated receptorgamma (PPARc) is a ligand-activated transcription factor with numerous biological effects. PPARc has been shown to exert a potential anti-inflammatory effect through suppression of TLR4-mediated inflammation. Therefore, PPARc agonists may have a potential to combat inflammatory conditions in pathologic states. The current study aims to show the decrease of inflammation by overexpression of PPARc in a cell reporter model. To reach this goal, recombinant pBudCE4.1 (?) containing encoding sequences of human TLR4 and MD2 was constructed and used to transfect HEK cells. Subsequently, inflammation was induced by LPS treatment as control group. In the treatment group, overexpression of PPARc prior to inflammation was performed and the expression of inflammatory markers was assessed in this condition. The expression of inflammatory markers (TNFa and iNOS) was defined by quantitative real time PCR and the amount of phosphorylated NF-jB was measured by western blot. Data indicated expression of TNFa and iNOS increased in LPS induced inflammation of stably transformed HEK cells with MD2 and TLR4. In this cell reporter model overexpression of PPARc dramatically prevented LPSinduced inflammation through the blocking of TLR4/ NF-jB signaling. PPARc was shown to negatively regulate TLR4 activity and therefore exerts its antiinflammatory action against LPS induced inflammation.

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“…The PPARg agonist activity of some ARBs, including candesartan, may not be independent of their AT 1 R-blocking properties. There is cross-talk between AT 1 R and PPARg activation (Xiao et al, 2009); PPARg agonists reduce AT 1 R-mediated inflammation and hypertension in vivo (Ji et al, 2009), and downregulates AT 1 R expression (Zhao et al, 2008), whereas Ang II, by stimulating the AT 1 R, downregulates PPARg activity (Tham et al, 2002). Further studies are necessary to elucidate the relative role of AT 1 R inhibition and PPARg activation in neuroprotection after TBI.…”

Section: Neuroprotection By Candesartan After Tbimentioning

confidence: 99%

Candesartan, an Angiotensin II AT1-Receptor Blocker and PPAR-γ Agonist, Reduces Lesion Volume and Improves Motor and Memory Function After Traumatic Brain Injury in Mice

Villapol

Yaszemski

Logan

et al. 2012

Neuropsychopharmacol

106

107

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Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT 1 R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFb1 while increasing expression of TGFb3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARg) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARg activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT 1 R-blocking and PPARg activation properties may have therapeutic value in treating TBI.

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PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

Cited by 80 publications

References 45 publications

Effects of PPAR.GAMMA. on hypertension, atherosclerosis, and chronic kidney disease

Effects of PPAR.GAMMA. on hypertension, atherosclerosis, and chronic kidney disease

PPARγ ameliorated LPS induced inflammation of HEK cell line expressing both human Toll-like receptor 4 (TLR4) and MD2

Candesartan, an Angiotensin II AT1-Receptor Blocker and PPAR-γ Agonist, Reduces Lesion Volume and Improves Motor and Memory Function After Traumatic Brain Injury in Mice

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