PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells

Zhao, Caiyan; Chen, Wei; Yang, Liu; Chen, Lihong; Stimpson, Stephen A.; Diehl, Anna Mae

doi:10.1016/j.bbrc.2006.09.069

Cited by 130 publications

(117 citation statements)

References 24 publications

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“…The stimulation of a PPAR-responsive element in the DR-reporter after COX-2 overexpression demonstrates this pathway. There are reports of inhibitory effects of PPAR-g on the TGF/Smad pathway and also on the block of TGFb-induced mitoinhibition (Han et al, 2004;Zhao et al, 2006). Therefore, the direct PGE as well as the PPAR-mediated effects can explain the effects of COX-2 overexpression on the TGF-b pathway.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 overexpression abrogates the antiproliferative effects of TGF-β

Enders

2007

Br J Cancer

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The influence of cyclooxygenase-2 (COX-2) overexpression on the development of tumours has been well documented. The underlying mechanism however has still not been completely elucidated. An escape of proliferating cells from the regulatory influence of TGF-b for example in the intestine has been discussed as well as a preponderance or prolongation of growth factor stimulation. The experiments presented here demonstrated that COX-2 transfection of a TGF-b-sensitive cell line abrogates the growth inhibitory effects of TGF-b. However, analysis of the TGF-b/Smad-signalling pathway clearly revealed that COX-2 overexpression did not interfere with that. Neither TGF-receptor expression nor Smad phosphorylation and signal transfer into the nucleus were influenced by COX-2 overexpression. In addition, a TGF-b reporter assay revealed no difference between controls and COX-2-transfected cells. Thus, the proliferation inhibiting effects must have been well compensated by growth-inducing stimuli. Indications for this came from experiments showing an induction of TGF-a expression and secretion with a higher and prolonged stimulation of the ERK 1/2 (p42/44) pathway in COX-2 transfectants. This effect could have been triggered by direct prostaglandin receptor stimulation or changes in intracellular lipid mediators. An increase in PPAR signalling as proven by a reporter assay is indication for the latter. Therefore, inhibiting both COX-2 as well as the PPAR and TGF/EGF pathway could be effective in the inhibition of adenoma or even carcinoma development in the intestine.

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 overexpression abrogates the antiproliferative effects of TGF-β

Enders

2007

Br J Cancer

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“…PPAR-g agonists inhibit TGF-b1-CTGF signaling, OPN expression, and the activity of MMP-2 and MMP-9. 6,7,37,38 On the other hand, ARBs usually inhibit TGF-b1-CTGF signaling and OPN activity, but do not affect MMP-2 or MMP-9 activity. [39][40][41][42] Thus, Telmisartan is a unique ARB that possesses potent anti-fibrotic activity via inhibition of MMP activation, OPN expression and TGF-b1-CTGF signaling.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…[3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well as anti-fibrotic activity by inhibiting transforming growth factor b-1 (TGF-b1) signaling, and the activity of matrix metalloprotease (MMP)-2/9 and the osteopontin (OPN). [6][7][8][9] Telmisartan is a structurally unique ARB that acts as a partial PPAR-g agonist (activating the receptor 25-30% of the maximum level achieved by full PPAR-g agonists) as well as an ARB, 10 thereby improving insulin resistance and lipid metabolism as well as reducing the blood pressure. 11,12 However, the effect of Telmisartan on the development of unfavorable LV remodeling after MI has not been investigated.…”

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confidence: 99%

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Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-g (PPAR-g) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-g agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-g antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor b-1 (TGF-b1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-g and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-g and TIMP-1, and inhibition of TGF-b1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-g activation were suggested to be important in addition to suppression of Ang II activity. Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by hypertrophy associated with interstitial fibrosis of the noninfarcted myocardium, and causes LV dilatation and cardiac dysfunction. It is known that angiotensin II (Ang II) has a crucial role in the development of unfavorable LV remodeling, and recent studies based on animal experiments have demonstrated that treatment with an Ang-converting enzyme inhibitor (ACE-I) and/or Ang II type I receptor blocker (ARB) can attenuate unfavorable LV remodeling. 1,2 Moreover, other experimental studies suggested that activation of peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor, improves unfavorable LV remodeling after MI. [3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well ...

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“…52 Endogenous nitrated fatty acids are potent agonists of peroxisome proliferator-activated receptor g, which have been shown to exhibit antifibrotic activity in the lung through SMAD inhibition. 65,66 Cultured IPF myofibroblasts treated with the most common nitrated fatty acids in human plasma, 10-nitro-oleic acid, increased peroxisome proliferator-activated receptor g expression, while reversing myofibroblast differentiation, as assessed by a-SMA levels and contractility. 50 More important, intratrachael treatment of mice with 10-nitro-oleic acid for 7 successive days beginning 21 days after bleomycin injection reduced the total lung collagen content and a-SMA protein levels.…”

Section: Role Of Dedifferentiation In Removing Myofibroblastsmentioning

confidence: 99%