Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation

Yoshida, Takafumi; Yamagishi, Sho‐ichi; Nakamura, Kazuo; Matsui, Takanori; Imaizumi, Tsutomu; Takeuchi, Masayoshi; Koga, Hironori; Ueno, Takato; Sata, Michio

doi:10.1007/s00125-006-0437-7

Cited by 108 publications

(67 citation statements)

References 10 publications

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“…Indeed, in a recent study, Yoshida et al [19] demonstrated that telmisartan improves IR in advanced glycation endproduct (AGE)-exposed human hepatoma (Hep3B) cells by decreasing serine phosphorylation and enhancing tyrosine phosphorylation of insulin-receptor substrate-1 but, when antagonized with an inhibitor of PPARγ, it loses these properties. Other animal studies [20][21][22][23] provided additional evidence of properties of telmisartan linking it to PPAR modulation that can account for its effects in steatohepatitis, for example a partial PPAR-α agonist activity which seems to be restricted to the liver, regulating serum adipokines with increased adiponectin and decreased resistin levels, and even anti-inflammatory properties.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis

Georgescu¹,

Ionescu²,

Niculescu³

et al. 2009

WJG

160

127

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AIM:To evaluate insulin resistance, cytolysis and nonalcoholic steatohepatitis (NASH) score (NAS) using the Kleiner and Brunt criteria in 54 patients with NASH and mild-to-moderate hypertension, treated with telmisartan vs valsartan for 20 mo. METHODS:All patients met the NCEP-ATP Ⅲ criteria for metabolic syndrome. Histology confirmed steatohepatitis, defined as a NAS greater than five up to 3 wk prior inclusion, using the current criteria. Patients with viral hepatitis, chronic alcohol intake, drug abuse or other significant immune or metabolic hepatic pathology were excluded. Subjects were randomly assigned either to the valsartan (V) group (standard dose 80 mg o.d., n = 26), or to the telmisartan (T) group (standard dose 20 mg o.d., n = 28). Treatment had to be taken daily at the same hour with no concomitant medication or alcohol consumption allowed. Neither the patient nor the medical staff was aware of treatment group allocation. Paired liver biopsies obtained at inclusion (visit 1) and end of treatment (EOT) were assessed by a single blinded pathologist, not aware of patient or treatment group. Blood pressure, BMI, ALT, AST, HOMA-IR, plasma triglycerides (TG) and total cholesterol (TC) were evaluated at inclusion and every 4 mo until EOT (visit 6). RESULTS:At EOT we noticed a significant decrease in ALT levels vs inclusion in all patients and this decrease did not differ significantly in group T vs group V. HOMA-IR significantly decreased at EOT vs inclusion in all patients but in group T, the mean HOMA-IR decrease per month was higher than in group V. NAS significantly diminished at EOT in all patients with a higher decrease in group T vs group V. CONCLUSION:Angiotensin receptor blockers seem to be efficient in hypertension-associated NASH. Telmisartan showed a higher efficacy regarding insulin resistance and histology, perhaps because of its specific PPAR-gamma ligand effect.

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Section: Discussionmentioning

confidence: 99%

Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis

Georgescu¹,

Ionescu²,

Niculescu³

et al. 2009

WJG

160

127

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“…16 Besides, telmisartan inhibited AGE-induced ROS generation via PPAR␥ activation in human hepatoma Hep3B cells. 36 PPAR␥, a ligand-activated transcription factor belonging to the nuclear receptor superfamily, regulates gene expression of key proteins involved in lipid metabolism, vascular inflammation, and proliferation, providing protection against atherosclerosis and coronary events. 37 Recently, Yang et al 38 have demonstrated that PPAR␥ activation lowers the ROS levels through coordinated transcriptional control of a set of proteins and enzymes involved in ROS metabolism.…”

Section: Discussionmentioning

confidence: 99%

Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System

et al. 2008

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Abstract-Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT 1 R), activates peroxisome proliferator activated receptor ␥ (PPAR␥) signaling that interferes with nitric oxide (NO) system. Because aging of endothelial cells (ECs) is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-system through blocking AT 1 R and activating PPAR␥ signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPAR␥ antagonist) until the twelfth passage. During the process of aging, PPAR␥ protein expression decreased significantly, whereas the expression of AT 1 R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F 2␣ formation. This effect was associated with an upregulated activity and protein expression of DDAH, accompanied by a decrease in ADMA concentration, an increase in NO metabolites, and delayed senescence. Blockade of PPAR␥ signaling by GW9662 or PPAR␥ small-interference RNA prevented the effect of telmisartan on ADMA-DDAH-NO system. Coincubation with Ang II did not affect the effect of telmisartan-delayed senescence, whereas Ang II itself accelerated endothelial aging. Moreover, AT 1 R blocker eprosartan that did not influence PPAR␥ protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPAR␥ signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan translationally and posttranslationally upregulated DDAH expression via activation of PPAR␥ signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence. Key Words: telmisartan Ⅲ angiotensin II type 1 receptor Ⅲ peroxisome proliferator activated receptor ␥ Ⅲ oxidative stress Ⅲ asymmetrical dimethylarginine Ⅲ nitric oxide Ⅲ aging A ging is a well-documented risk factor for cardiovascular diseases. One of the possible physiopathological mechanisms through which increasing age may lead to cardiovascular damage is the promotion of endothelial dysfunction. 1 Aged human endothelial cells (ECs), which produce less NO, more asymmetrical dimethylarginine (ADMA), a novel cardiovascular risk factor, and more reactive oxygen species (ROS), 2-5 could account for endothelial dysfunction and development of cardiovascular diseases. 6 -10 We and other have previously demonstrated that aging of human ECs can be altered by several different factors contributing to delay or accelerate the process of aging. [2][3][4][5]11,12 These results suggest that the process of endothelial aging may be an influenceable process and raise the possibility of therapies for preventing various cardiovascular diseases in the elderly.Telmisartan, a highly lipophilic angiotensin (Ang) II type 1 receptor (AT 1 R) blocker (ARB), is used for the treatme...

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“…that some ARBs (including OLM) (Yoshida et al 2006;Yamagishi et al 2008) and nifedipine, another dihydropyridine CCB, also suppress the AGEs-RAGE expressions (Matsui et al 2010). It was previously reported that OLM reduces serum levels of the RAGE ligands, such as AGEs (Nangaku et al 2003) and N-(epsilon)-carboxymethyllysine (CML) (Honda et al 2012), and that AZL also reduces AGEs (Nakamura et al 2011).…”

Section: Anti-oxidant Effects Of Olm Plus Azlmentioning

confidence: 99%

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Noda

Hosoya

Nakajima

et al. 2012

Tohoku J. Exp. Med.

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Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE −/− ) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE −/− mice. Diabetic ApoE −/− mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE −/− mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.

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Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation

Cited by 108 publications

References 10 publications

Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis

Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis

Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

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