Preventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation in Patients With Type 2 Diabetes

Choi, Donghoon; Kim, Soo‐Kyung; Choi, Sung Hee; Ko, Young Guk; Ahn, Chul Woo; Jang, Yangsoo; Lim, Sung Kil; Lee, Hyun Chul; Soo, Bong

doi:10.2337/diacare.27.11.2654

Cited by 245 publications

(136 citation statements)

References 41 publications

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“…Rosiglitazone treatment for 12 weeks reduced IMT and ameliorated the internal diameter in SHR aortas (Fig. 6, A-C), which was consistent with previous studies (26,27). These data indicate that improving PPAR-␥ expression with rosiglitazone ameliorate the aortic remodeling induced by hypertension.…”

Section: Vsmc Phenotypicsupporting

confidence: 82%

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Zhang

Xie

Wang

et al. 2010

Journal of Biological Chemistry

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The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-␥ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-␥ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, ␣-smooth muscle actin (␣-SMA) and smooth muscle 22␣ (SM22␣), and enhanced proliferation and migration. PPAR-␥ overexpression rescued the expression of ␣-SMA and SM22␣, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-␥ silencing exerted the opposite effect. Activating PPAR-␥ using rosiglitazone in vivo up-regulated aortic ␣-SMA and SM22␣ expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-␥ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-␥ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-␥ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-␥ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-␥ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.Hypertension and hypertension-induced vascular remodeling underlie numerous cardiovascular disorders. Activated vascular smooth muscle cells (VSMCs) 2 are essential contributors to this vascular remodeling (1). Unlike other muscle cells, VSMCs do not terminally differentiate. They can switch from a differentiated phenotype (also known as contractile or quiescent phenotype) to a dedifferentiated phenotype (also known as synthetic or activated phenotype) in response to vascular injury. In this process, VSMCs regain their proliferative and migratory capacities, secrete matrix proteins, and down-regulate smooth muscle contractile proteins, such as ␣-smooth muscle actin (␣-SMA), smooth muscle 22␣ (SM22␣), smooth muscle myosin heavy chain, and calponin (2). Although this phenotypic modulation is undoubtedly required for vascular repair, inappropriate modulation is associated with increased vascular resistance and aggravates vascular injury. However, despite intensive research efforts, the precise mechanisms underlying VSMC phenotypic modula...

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Section: Vsmc Phenotypicsupporting

confidence: 82%

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Zhang

Xie

Wang

et al. 2010

Journal of Biological Chemistry

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“…This has been observed with lifestyle changes (40,41), as well as with chronic treatment with drugs such as metformin (42) and, to a greater extent, glitazones (43). Interestingly, metformin was the only pharmacological agent achieving a significant prevention of CVD in the UK Prospective Diabetes Study (UKPDS) (44), and glitazones have been shown to reduce carotid intima-media thickness (45) and to prevent coronary restenosis after angioplasty (46) and perhaps reduce risk for CVD in type 2 diabetes (32).…”

Section: Discussionmentioning

confidence: 99%

Insulin Resistance as Estimated by Homeostasis Model Assessment Predicts Incident Symptomatic Cardiovascular Disease in Caucasian Subjects From the General Population

Bonora

Kiechl²,

Willeit³

et al. 2007

Diabetes Care

313

209

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OBJECTIVE -The purpose of this study was to evaluate whether insulin resistance is associated to cardiovascular disease (CVD) and to understand whether this association can be explained by traditional and novel CVD risk factors associated with this metabolic disorder. RESEARCH DESIGN AND METHODS-We examined a sample representative of the population of Bruneck, Italy (n ϭ 919; aged 40 -79 years). Insulin-resistant subjects were those with a score in the top quartile of the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR). Risk factors correlated with insulin resistance included BMI, A1C, HDL cholesterol, triglycerides, blood pressure, high-sensitivity C-reactive protein (hsCRP), fibrinogen, oxidized LDL, vascular cell adhesion molecule-1 (VCAM-1), and adiponectin. Subjects without CVD at baseline were followed up for 15 years for incident CVD, a composite end point including fatal and nonfatal myocardial infarction and stroke, transient ischemic attack, and any revascularization procedure.RESULTS -During follow-up, 118 subjects experienced a first symptomatic CVD event. Levels of HOMA-IR were higher at baseline among subjects who developed CVD (2.8) compared with those remaining free of CVD (2.5) (P Ͻ 0.05). Levels of HOMA-IR also were significantly correlated (P Ͻ 0.05) with most CVD risk factors we evaluated. In Cox proportional hazard models, insulin-resistant subjects had an age-, sex-, and smoking-adjusted 2.1-fold increased risk (95% CI 1.3-3.1) of incident symptomatic CVD relative to non-insulin-resistant subjects. After sequential adjustment for physical activity and classic risk factors (A1C, LDL cholesterol, and hypertension) as well as BMI, HDL cholesterol, triglycerides, and novel risk factors, including fibrinogen, oxidized LDL, hsCRP, VCAM-1, and adiponectin, the association between HOMA-IR and incident CVD remained significant and virtually unchanged (hazard ratio 2.2 [95% CI 1.4 -3.6], P Ͻ 0.001).CONCLUSIONS -HOMA-estimated insulin resistance is associated with subsequent symptomatic CVD in the general population independently of all classic and several nontraditional risk factors. These data suggest that insulin resistance may be an important target to reduce CVD risk. Diabetes Care 30:318 -324, 2007I nsulin resistance is a pathogenic factor for type 2 diabetes (1,2) and is associated with diverse cardiovascular disease (CVD) risk states, including obesity, essential hypertension, hypertriglyceridemia, and low HDL cholesterol (3). A significant proportion of apparently healthy subjects also are insulin resistant (4,5). In aggregate, insulin resistance and related conditions are very common, affecting as many as 30 -40% of subjects living in affluent countries. Insulin resistance is also a common finding in developing countries. Throughout the world hundreds of millions of people and perhaps even Ͼ1 billion people are estimated to have insulin resistance (6).In recent years the question as to whether insulin resistance is involved in the pathogenesis of CVD has persisted. This ...

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“…In persons with type 2 diabetes treated with rosiglitazone (68) and in nondiabetic persons with coronary artery disease treated with pioglitazone (69), restenosis rates have been reduced. In the latter study, there was no effect on glucose, insulin, A1C, or lipids but significant reduction in neointimal volume.…”

Section: Coagulationmentioning

confidence: 99%

Third Annual World Congress on the Insulin Resistance Syndrome

Bloomgarden

2006

Diabetes Care

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Preventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation in Patients With Type 2 Diabetes

Cited by 245 publications

References 41 publications

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Insulin Resistance as Estimated by Homeostasis Model Assessment Predicts Incident Symptomatic Cardiovascular Disease in Caucasian Subjects From the General Population

Third Annual World Congress on the Insulin Resistance Syndrome

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