Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect.

Buchanan, Thomas A.; Meehan, Woemer P.; Jeng, Young Y.; Yang, Dong; Chan, Timothy M.; Nadler, Jerry L.; Scott, S. D.; Rude, Robert K.; Hsueh, Willa A.

doi:10.1172/jci118041

Cited by 228 publications

(137 citation statements)

References 38 publications

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“…In this context, the induction of ACS expression by BRL 49653 is however difficult to explain. One must however bear in mind that not all of the effects of the thiazolidinediones are mediated via PPAR␥ activation, and it is has been shown that these agents activate several other signaling pathways (52)(53)(54). Further investigations need to address whether ACS expression, unlike FATP or LPL expression, is subject to such a regulatory circuit.…”

Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARα and PPARγ Activators

Martin

Schoonjans

Lefebvre

et al. 1997

Journal of Biological Chemistry

484

295

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Intracellular fatty acid (FA) concentrations are in part determined by a regulated import/export system that is controlled by two key proteins, i.e. fatty acid transport protein (FATP) and acyl-CoA synthetase (ACS), which respectively facilitate the transport of FAs across the cell membrane and their esterification to prevent their efflux. The aim of this investigation was to analyze the expression pattern of FATP and ACS and to determine whether their expression was altered by agents that affect FA metabolism through the activation of peroxisome proliferator-activated receptors (PPAR) such as the fibrates and thiazolidinediones. FATP mRNA was ubiquitously expressed, with highest levels being detected in adipose tissue, heart, brain, and testis. Fibrate treatment, which is known to preferentially activate PPAR␣, induced FATP mRNA levels in rat liver and intestine and induced ACS mRNA levels in liver and kidney. The antidiabetic thiazolidinedione BRL 49653, which is a high-affinity ligand for the adipocyte-specific PPAR␥ form, caused a small induction of muscle but a robust induction of adipose tissue FATP mRNA levels. BRL 49653 did not affect liver FATP and had a tendency to decrease heart FATP mRNA levels. ACS mRNA levels in general showed a similar pattern after BRL 49653 as FATP except for the muscle where ACS mRNA was induced. This regulation of FATP and ACS expression by PPAR activators was shown to be at the transcriptional level and could also be reproduced in vitro in cell culture systems. In the hepatocyte cell lines AML-12 or Fa 32, fenofibric acid, but not BRL 49653, induced FATP and ACS mRNA levels, whereas in the 3T3-L1 preadipocyte cell line, the PPAR␥ ligand induced FATP and ACS mRNA levels quicker than fenofibric acid. Inducibility of ACS and FATP mRNA by PPAR␣ or ␥ activators correlated with the tissue-specific distribution of the respective PPARs and was furthermore associated with a concomitant increase in FA uptake. Most interestingly, thiazolidinedione antidiabetic agents seem to favor adipocyte-specific FA uptake relative to muscle, perhaps underlying in part the beneficial effects of these agents on insulin-mediated glucose disposal.

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Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARα and PPARγ Activators

Martin

Schoonjans

Lefebvre

et al. 1997

Journal of Biological Chemistry

484

295

View full text Add to dashboard Cite

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“…As insulin sensitizers these agents could lower blood pressure indirectly by improving insulin resistance [17]. Thiazolidinediones have also been shown to have direct effects on the vasculature [18] and VSMCs [3,19]. It is possible, therefore, that troglitazone and other thiazolidinediones may regulate blood pressure more directly by interfering with the action of growth factors, such as All, involved in the development of hypertension.…”

Section: Referencesmentioning

confidence: 99%

Troglitazone inhibits angiotensin II‐induced DNA synthesis and migration in vascular smooth muscle cells

Graf

Hsueh

et al. 1997

FEBS Letters

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Angiotensin Π (All) plays a crucial role in controlling the proliferation and migration of vascular smooth muscle cells (VSMCs). The present study was undertaken to determine if troglitazone (Tro) has an effect on the G-protein coupled signaling through All type I (AT-1) receptors in cultured rat aortic VSMCs. All-induced MAP kinase activation was inhibited 67.9% by Tro. All-induced DNA synthesis and migration was completely inhibited by Tro or by the AT-1 receptor blocker irbesartan. The present study demonstrates that troglitazone inhibits All-induced DNA synthesis, migration and MAP kinase activation in VSMCs which are important molecular events for the development of neointimal hyperplasia and atherosclerosis.

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“…TZDs (ie, troglitazone, ciglitazone, pioglitazone, and rosiglitazone) activate PPAR␥, leading to improved insulin sensitivity and reduced blood pressure in both humans and animals through a mechanism that has not been completely elucidated. [3][4][5][6] These findings, coupled with the observation that PPAR␥ is expressed in both vascular muscle 7 and endothelium, 8 suggest that it may play an important role in the regulation of blood pressure and vascular tone. Indeed, patients with mutations in PPAR␥ imparting dominant negative activity on the receptor, exhibit early onset hypertension and insulin resistance.…”

mentioning

confidence: 98%

PPARγ Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice

et al. 2004

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Abstract-The peroxisome proliferator activated receptor (PPAR␥) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R ϩ A ϩ ). Rosiglitazone decreased systolic (138Ϯ5 versus 128Ϯ5 mm Hg) and mean blood pressure (145Ϯ5 versus 126Ϯ7 mm Hg) of R ϩ A ϩ mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R ϩ A ϩ mice when compared with littermate controls (RA Ϫ ). There were no effects of rosiglitazone on RA Ϫ mice; however, relaxation to acetylcholine (49Ϯ10 versus 82Ϯ9% at 100 mol/L) and nitric oxide (51Ϯ11 versus 72Ϯ6% at 10 mol/L) was significantly improved in treated R ϩ A ϩ mice. Rosiglitazone treatment of R ϩ A ϩ mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein.In separate studies, carotid arteries from R ϩ A ϩ and RA Ϫ mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPAR␥-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester (200 mol/L) or the PPAR␥ antagonist bisphenol A diglycidyl ether; 4,4Ј-isopropylidenediphenol diglycidyl ether (100 mol/L). These data suggest that in addition to potential genomic regulation caused by PPAR␥ activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function. Key Words: nitric oxide Ⅲ angiotensin Ⅲ endothelin Ⅲ carotid P eroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and bind to DNA as a heterodimer with retinoid x receptor to regulate transcription. Three genes encode different PPARs (␣, ␤/␦, and ␥), and the gene products are differentially expressed in a variety of tissues. 1 PPARs have been most widely characterized with respect to their role in adipocyte growth and differentiation. 2 More recently, PPAR␥ has become the focus of attention for the treatment of noninsulin-dependent diabetes mellitus, due largely to successful treatment with the thiazolidinedione (TZD) class of drugs that act as specific PPAR␥ ligands. TZDs (ie, troglitazone, ciglitazone, pioglitazone, and rosiglitazone) activate PPAR␥, leading to improved insulin sensitivity and reduced blood pressure in both humans and animals through a mechanism that has not been completely elucidated. [3][4][5][6] These findings, coupled with the observation that PPAR␥ is expressed in both vascular muscle 7 and endothelium, 8 suggest that it may play an important role in the regulati...

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Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect.

Cited by 228 publications

References 38 publications

Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARα and PPARγ Activators

Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARα and PPARγ Activators

Troglitazone inhibits angiotensin II‐induced DNA synthesis and migration in vascular smooth muscle cells

PPARγ Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice

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