Atherosclerosis and cardiovascular risk reduction with PPAR agonists

Andrulionytė, Laura; Laakso, Markku

doi:10.1007/s11883-007-0033-4

Cited by 10 publications

(6 citation statements)

References 55 publications

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“…A role for PPARγ has also been reported in the regulation of vascular tone, with PPARγ ligands inhibiting ET-1 and AT-1R expression while reducing the impact of excessive oxidative and nitrative stress [54,71]. PPARγ agonists increase AT-2R expression [54,71], and promote NO production and release [54,71,189,190], which, in turn, can activate PPARγ activity via MAPK [190]. Other studies suggest that PPARγ agonists reduce VEGF secretion, modulate VEGF-induced angiogenesis and inhibit VEGF-induced migration of endothelial cells.…”

Section: Pparsmentioning

confidence: 99%

“…However, whether or not currently used TZDs, pioglitazone and rosiglitazone, are protective of CVD in humans is questionable [223–225]. Until now only a few large clinical trials have reported the effects of TZDs on cardiovascular events and the findings differ considerably as summarized in Table 12 [156,158,189,193,200]. …”

Section: Ppar Ligands/agonists and Their Relevance To Mets T2dm And Cvdmentioning

confidence: 99%

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Peroxisome proliferator-activated receptors, Metabolic Syndrome and Cardiovascular Disease

Azhar

2010

Future Cardiol.

124

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Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/β and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones.

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Section: Pparsmentioning

confidence: 99%

Section: Ppar Ligands/agonists and Their Relevance To Mets T2dm And Cvdmentioning

confidence: 99%

Peroxisome proliferator-activated receptors, Metabolic Syndrome and Cardiovascular Disease

Azhar

2010

Future Cardiol.

124

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“…The significant benefit of the fenofibrate-simvastatin combination therapy over statins alone regarding the incidence of major cardiovascular events in patients with atherogenic ‘mixed’ dyslipidemia (moderate hypertriglyceridemia and low HDL-cholesterol) was especially important [23]. Moreover, there is accumulating evidence supporting a direct protective role for PPARα agonists in cardiomyocytes via the PPARα/IGF-1 pathway, an effect though, needing further investigation in humans [19]–[21], [24].…”

Section: Introductionmentioning

confidence: 99%

Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis

et al. 2013

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Stress is a risk factor for several cardiovascular pathologies. PPARα holds a fundamental role in control of lipid homeostasis by directly regulating genes involved in fatty acid transport and oxidation. Importantly, PPARα agonists are effective in raising HDL-cholesterol and lowering triglycerides, properties that reduce the risk for cardiovascular diseases. This study investigated the role of stress and adrenergic receptor (AR)-related pathways in PPARα and HNF4α regulation and signaling in mice following repeated restraint stress or treatment with AR-antagonists administered prior to stress to block AR-linked pathways. Repeated restraint stress up-regulated Pparα and its target genes in the liver, including Acox, Acot1, Acot4, Cyp4a10, Cyp4a14 and Lipin2, an effect that was highly correlated with Hnf4α. In vitro studies using primary hepatocyte cultures treated with epinephrine or AR-agonists confirmed that hepatic AR/cAMP/PKA/CREB- and JNK-linked pathways are involved in PPARα and HNF4α regulation. Notably, restraint stress, independent of PPARα, suppressed plasma triglyceride levels. This stress-induced effect could be attributed in part to hormone sensitive lipase activation in the white adipose tissue, which was not prevented by the increased levels of perilipin. Overall, this study identifies a mechanistic basis for the modification of lipid homeostasis following stress and potentially indicates novel roles for PPARα and HNF4α in stress-induced lipid metabolism.

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“…PPARs are presumed therapeutic targets in CVD (21). A word of caution: at present the clinical trials have not produced convincing evidence that CVD is prevented with the use of PPARalpha and PPARgamma agonists (22).…”

Section: Fibratesmentioning

confidence: 99%

Update on medical management of dyslipidemia and atherosclerosis

Ginter

Simko²

2013

BLL

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Scientifi c achievements revealing the pathogenesis of atherosclerosis resulted in the second half of the 20th century in major improvement in prevention and therapy of cardiovascular disorders (CVD). Essential became the understanding of a critical pathogenetic role of the low-density lipoproteins (LDL), mainly their oxidized form (oxLDL) and also the protective potential of the high-density lipoproteins (HDL). CVD is now regarded to be an infl ammatory disease in which a systemic infl ammatory reaction is combined with an accumulation of immune cells in atherosclerotic plaques. Higher intake of antioxidants in fruit and vegetable, life style modifications, cessation of smoking, physical exercise and introduction of medications that lower LDL and promote HDL (statins, niacin and fi brates) resulted in a substantial decline of the killer effect of unmanaged CVD. In the United Kingdom the male CVD mortality declined between 1970 and 2009 from 700 to 200 deaths per 100,000. In France, CVD mortality in the middle age population (25-64 years) is now responsible for death in only 15 % men and in 11 % women. Unfortunately, in many parts of the world CVD mortality remains a prominent population scourge. Recent dicoveries, especially on the role of peroxisome proliferator-activated receptors (PPAR) and antisense compounds used in addition to established anti-atherogenic medications, promise further gains in the fi ght against atherosclerosis (Fig. 4, Ref. 54). Full Text in PDF www.elis.sk.

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Atherosclerosis and cardiovascular risk reduction with PPAR agonists

Cited by 10 publications

References 55 publications

Peroxisome proliferator-activated receptors, Metabolic Syndrome and Cardiovascular Disease

Peroxisome proliferator-activated receptors, Metabolic Syndrome and Cardiovascular Disease

Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis

Update on medical management of dyslipidemia and atherosclerosis

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