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Review
. 2012 Feb 20;3(1):11-23.
doi: 10.1111/j.2040-1124.2011.00182.x.

Thiazolidinedione-independent activation of peroxisome proliferator-activated receptor γ is a potential target for diabetic macrovascular complications

Takeshi Matsumura  1 , Kayo Taketa  1 , Seiya Shimoda  1 , Eiichi Araki  1
Affiliations
Review

Thiazolidinedione-independent activation of peroxisome proliferator-activated receptor γ is a potential target for diabetic macrovascular complications

Takeshi Matsumura et al. J Diabetes Investig. .

Abstract

Macrovascular complications are responsible for the high morbidity and mortality in patients with diabetes. Peroxisome proliferator-activated receptor γ (PPARγ) plays a central role in the process of adipocyte differentiation and insulin sensitization, and also possesses anti-atherogenic effects. Recently, some statins, angiotensin II type 1 receptor blockers and calcium channel blockers have been reported to activate PPARγ. However, the impact of PPARγ activation on diabetic macrovascular complications is not fully understood. It has been reported that the activation of PPARγ by thiazolidinediones induces anti-atherogenic effects in vascular cells, including monocytes/macrophages, endothelial cells and smooth muscle cells, in atherosclerotic animal models and in clinical studies. We have reported that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which are used for treatment of hypercholesterolemia, activate PPARγ and mediate anti-atherogenic effects through PPARγ activation in macrophages. Also, telmisartan, an angiotensin type I receptor blocker, has been reported to have anti-atherogenic effects through PPARγ activation. Furthermore, we have reported that nifedipine, a dihydropyridine calcium channel blocker, can activate PPARγ, thereby mediating anti-atherogenic effects in macrophages. Therefore, statin therapy and part of anti-hypertensive therapy might produce beneficial effects through PPARγ activation in hypercholesterolemic and/or hypertensive patients with diabetes, and PPARγ might be a therapeutic target for diabetic macrovascular complications. In the present review, we focus on the anti-atherogenic effects of PPARγ and suggest potential therapeutic approaches to prevent diabetic macrovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00182.x, 2012).

Keywords: Diabetes; Macroangiopathy; Peroxisome proliferator‐activated receptor γ.

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Figures

Figure 1
Figure 1
Anti‐atherogenic effects of thiazolidinediones (TZD) in vascular cells. ABCA1, adenosine triphosphate‐binding cassette transporter A1; ABCG1, adenosine triphosphate‐binding cassette transporter G1; AT1R, angiotensin II type 1 receptor; COX‐2, cyclooxygenase‐2; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; ET‐1, endothelin‐1; ICAM‐1, intercellular adhesion molecule‐1; IL‐1β, interleukin‐1β; IL‐6, interleukin‐6; iNOS, inducible NO synthase; LXR, liver X receptor; Mϕ, macrophage; MCP‐1, monocyte chemoattractant protein‐1; MMP‐9, matrix metalloproteinase‐9; Mo, Monocyte; NO, nitric oxide; PAI‐1, plasminogen activator inhibitor‐1; ROS, reactive oxygen species; SMC, smooth muscle cell; TIMP‐1, tissue inhibitor of metalloproteinase‐1; TNF‐α, tumor necrosis factor‐α; VCAM‐1, vascular cell adhesion molecule‐1.
Figure 2
Figure 2
Summary of statin‐mediated peroxisome proliferator‐activated receptor γ (PPARγ) activation in macrophages. When treated with statins, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are downregulated by inhibition of the mevalonate pathway, thereby inhibiting geranylgeranylation and farnesylation, and the subsequent translocation of RhoA and Cdc42. The suppression of RhoA and Cdc42 translocation abrogates the RhoA and Cdc42 signaling pathways, thereby inducing p38 mitogen‐activated protein kinase (MAPK)‐dependent cyclooxygenase‐2 (COX‐2) production. In addition, small G protein‐independent extracellular signal‐regulated kinase 1/2 (ERK1/2) activation mediated by the suppression of geranylgeranylation and farnesylation is also involved in COX‐2 production. Overexpression of COX‐2 produces intracellular 15d‐PGJ2, which activates PPARγ. The activation of PPARγ mediates the downregulation of TNF‐α and MCP‐1 mRNA expression by inactivating AP‐1 and NF‐κB, and upregulating ABCA1. AA, arachidonic acid; ABCA1, adenosine triphosphate‐binding cassette transporter A1; AP‐1, activator protein‐1; HMG‐CoA, 3‐hydroxy‐3‐methylglutaryl coenzyme A; 15d‐PGJ2, 15‐deoxy‐Δ12,14‐prostaglandin J2; MCP‐1, monocyte chemoattractant protein‐1; NF‐κB, nuclear factor‐κB; TNF‐α, tumor necrosis factor‐α.
Figure 3
Figure 3
Anti‐atherogenic effects of telmisartan in vascular cells. ABCA1, adenosine triphosphate‐binding cassette transporter A1; ABCG1, adenosine triphosphate‐binding cassette transporter G1; AT1R, angiotensin II type 1 receptor; EC, endothelial cell; Mϕ, macrophage; MCP‐1, monocyte chemoattractant protein‐1; NF‐κB, nuclear factor‐κB; ROS, reactive oxygen species; SMC, smooth muscle cell; TNF‐α, tumor necrosis factor‐α; VCAM‐1, vascular cell adhesion molecule‐1.
Figure 4
Figure 4
Summary of nifedipine‐mediated peroxisome proliferator‐activated receptor γ (PPARγ) activation in macrophages. When macrophages are treated with nifedipine, extracellular‐signal regulated kinase 1/2 (ERK1/2) activity is downregulated. Inactivation of ERK1/2 suppresses PPARγ phosphorylation, leading to its activation. PPARγ activation blocks nuclear factor κB (NF‐κB) activity, downregulates monocyte chemoattractant protein‐1 (MCP‐1) expression and upregulates adenosine triphosphate‐binding cassette transporter A1 (ABCA1) expression. Nifedipine can therefore induce anti‐atherogenic action.
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References

    1. Abbott RD, Donahue RP, Kannel WB, et al. The impact of diabetes on survival following myocardial infarction in men vs women. The Framingham Study. JAMA 1988; 260: 3456–3460 - PubMed
    1. Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the US population, 1971–1993. Diabetes Care 1998; 21: 1138–1145 - PubMed
    1. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and non‐diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234 - PubMed
    1. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA 1979; 241: 2035–2038 - PubMed
    1. Pan WH, Cedres LB, Liu K, et al. Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women. Am J Epidemiol 1986; 123: 504–516 - PubMed

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