PPARγ Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells

Oyama, Yoshihiro; Akuzawa, Nobuhiro; Nagai, Ryozo; Kurabayashi, Masahiko

doi:10.1161/hh0302.105098

Cited by 58 publications

(38 citation statements)

References 39 publications

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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%

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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Section: Discussionmentioning

confidence: 99%

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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“…Pioglitazone decreased cardiac fibrosis, macrophage accumulation, and OPN expression in cPPAR␥ Ϫ/Ϫ , cPPAR␥ ϩ/ϩ , and mPPAR␥ ϩ/ϩ mice, suggesting that macrophage accumulation and OPN expression is a major mechanism of cardiac fibrosis induced by RAAS activation. PPAR␥ ligands suppress macrophage OPN expression (47), attenuate macrophage expression of several pro-inflammatory genes, and inhibit monocyte chemotaxis (48). Pioglitazone did not, however, attenuate cardiac fibrosis in mice with a monocyte-specific PPAR␥ deficiency, suggesting that PPAR␥ is required for the attenuation of monocyte inflammatory behavior that leads to cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

et al. 2008

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OBJECTIVE— Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis. RESEARCH DESIGN AND METHODS— Wild-type cardiomyocyte- and macrophage-specific PPARγ −/− mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARγ ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARγ in cardiac fibrosis. RESULTS— Cardiomyocyte-specific PPARγ −/− mice (cPPARγ −/− ) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARγ −/− mice but induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARγ–independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARγ −/− mice. CONCLUSIONS— We arrived at the following conclusions: 1 ) both cardiomyocyte-specific PPARγ deficiency and activation promote cardiac hypertrophy, 2 ) both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration, 3 ) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4 ) macrophage PPARγ activation prevents myocardial macrophage accumulation, and 5 ) PPARγ ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.

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“…Indeed, modulation of the nuclear receptor and transcription factor PPAR may not only regulate apolipoprotein expression and adipocyte differentiation, but in vitro studies show that stimulation of PPAR-␥ may also have antiinflammatory effects and suppress the generation of ROS (Table 1), probably by targeting NF-B. Moreover, as a PPAR-␥ agonist, troglitazone, reduces osteopontin gene expression (105), it could be hypothesized that PPAR-␥ agonists also inhibit plaque formation (106). Thus, as a recent clinical study shows that a PPAR-␥ agonist, rosiglitazone, reduces serum levels of both MMP-9 and CRP in patients with type 2 diabetes mellitus (107), it is evident that the use of this new class of insulin-sensitizing drugs may be a novel therapeutic strategy for reducing inflammation and atherosclerosis in ESRD patients.…”

Section: Inflammation and Oxidative Stress As Potential Therapeutic Tmentioning

confidence: 99%

Coronary Artery Disease in End-Stage Renal Disease

Stenvinkel

Pecoits‐Filho

Lindholm

2003

Journal of the American Society of Nephrology

213

169

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PPARγ Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells

Cited by 58 publications

References 39 publications

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

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

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

Coronary Artery Disease in End-Stage Renal Disease

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