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

Graf, Kristof; Xi, Xiao-Ping; Hsueh, Willa A.; Law, Ronald E.

doi:10.1016/s0014-5793(96)01371-3

Cited by 73 publications

(39 citation statements)

References 21 publications

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“…PPAR␥ is expressed in VSMC (16,17), and ligands for this nuclear receptor inhibit VSMC proliferation induced by several different mitogens in vitro (18,19) and intimal hyperplasia in vivo (18). These observations suggest that activation of PPAR␥ interferes with the function of a fundamental component of the cell cycle machinery.…”

Section: Proliferation Of Vascular Smooth Muscle Cells (Vsmc)mentioning

confidence: 97%

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Retinoblastoma Phosphorylation and G1 → S Transition in Vascular Smooth Muscle Cells

Wakino¹,

Kintscher²,

Kim³

et al. 2000

Journal of Biological Chemistry

206

179

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear receptor superfamily that is activated by binding certain fatty acids, eicosanoids, and insulin-sensitizing thiazolidinediones (TZD). The TZD troglitazone (TRO) inhibits vascular smooth muscle cell proliferation and migration both in vitro and in vivo. The precise mechanism of its antiproliferative activity, however, has not been elucidated. We report here that PPAR␥ ligands inhibit rat aortic vascular smooth muscle cell proliferation by blocking the events critical for G 1 3 S progression. Flow cytometry demonstrated that both TRO and another TZD, rosiglitazone, prevented G 1 3 S progression induced by platelet-derived growth factor and insulin. Movement of cells from G 1 3 S was also inhibited by the non-TZD, natural PPAR␥ ligand 15-deoxy-12,14 ⌬ prostaglandin J 2 (15d-PGJ 2 ), and the mitogen-activated protein kinase pathway inhibitor PD98059. Inhibition of G 1 3 S exit by these compounds was accompanied by a substantial blockade of retinoblastoma protein phosphorylation. TRO and rosiglitazone attenuated both the mitogen-induced degradation of p27 kip1 and the mitogenic induction of p21 cip1 . 15d-PGJ 2 and PD98059 inhibited both the degradation of p27 kip1 and the induction of cyclin D1 in response to mitogens. These effects resulted in the inhibition of mitogenic stimulation of cyclin-dependent kinases activated by cyclins D1 and E. These data demonstrate that PPAR␥ ligands are antiproliferative drugs that act by modulating cyclin-dependent kinase inhibitors; they may provide a new therapeutic approach for proliferative vascular diseases.

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Section: Proliferation Of Vascular Smooth Muscle Cells (Vsmc)mentioning

confidence: 97%

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Retinoblastoma Phosphorylation and G1 → S Transition in Vascular Smooth Muscle Cells

Wakino¹,

Kintscher²,

Kim³

et al. 2000

Journal of Biological Chemistry

206

179

View full text Add to dashboard Cite

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“…These agents also reduce the progression of intima-media thickness that commonly occurs in patients with atherosclerosis and, in some studies, decreases intima-media thickness per se (78,79). At least part of this action could be caused by interference with the mitogen-activated protein-kinase pathway (80). Microvascular effects.…”

Section: Potential Therapeutic Roles Of Ppar Agonists In Other Vasculmentioning

confidence: 99%

Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

2005

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Peroxisome proliferator-activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPAR␣ and -␥ are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPAR␣. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPAR␥, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPAR␥ agonists are therefore used to treat type 2 diabetes. PPAR␣ and -␥ agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPAR␣/␥ agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPAR␦, and its potential as a therapeutic target are currently under investigation.

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“…Although it is generally believed that TZDs exert insulin-sensitizing activity through the activation of peroxisome proliferator-activated receptor (PPAR)-␥, a member of the PPAR nuclear receptor superfamily (3), the exact mechanism of their action remains to be clarified (4)(5)(6). Besides its insulinsensitizing activity, troglitazone, one of the TZD compounds, was found to inhibit high glucose-induced proliferation and migration of vascular smooth muscle cells by inhibiting the activation of protein kinase C (PKC) (7); to inhibit platelet aggregation (8); to reduce balloon injury-induced intimal hyperplasia in rat artery (9); and to suppress both insulin-and angiotensin II-induced increase of DNA synthesis by inhibiting the activation of extracellular signal-regulated kinase (ERK) (10,11). Troglitazone was also shown to ameliorate albuminuria and peripheral neuropathy in streptozotocin (STZ)-induced diabetic rats, regardless of blood glucose levels (12,13).…”

Section: Thiazolidinedione Compounds Ameliorate Glomerular Dysfunctiomentioning

confidence: 99%

Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats.

et al. 2000

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Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent glomerular dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-␤1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without ␣-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent glomerular dysfunction through the inhibition of the DAG-PKC-ERK pathway. Diabetes 49:1022-1032, 2000 T hiazolidinediones (TZDs), novel insulin-sensitizing agents, have been shown to attenuate hyperinsulinemia and hyperglycemia in insulin-resistant diabetic animals and human subjects with type 2 diabetes (1,2). These agents are currently in clinical trials and have been widely used as oral antidiabetic agents in subjects with type 2 diabetes in the U.S. and other countries. Although it is generally believed that TZDs exert insulin-sensitizing activity through the activation of peroxisome proliferator-activated receptor (PPAR)-␥, a member of the PPAR nuclear receptor superfamily (3), the exact mechanism of their action remains to be clarified (4-6). Besides its insulinsensitizing activity, troglitazone, one of the TZD compounds, was found to inhibit high glucose-induced proliferation and migration of vascular smooth muscle cells by inhibiting the activation of protein kinase C (PKC) (7); to inhibit platelet aggregation (8); to reduce balloon injury-induced intimal hyperplasia in rat artery (9); and to suppress both insulin-and angiotensin II-induced increase of DNA synthesis by inhibiting the activation of extracellular signal-regulated kinase (ERK) (10,11). Troglitazone was also shown to ameliorate albuminuria and peripheral neuropathy in streptozotocin (STZ)-induced diabetic rats, regardless of blood glucose levels (12,13). These results indicate ...

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

Cited by 73 publications

References 21 publications

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Retinoblastoma Phosphorylation and G1 → S Transition in Vascular Smooth Muscle Cells

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Retinoblastoma Phosphorylation and G1 → S Transition in Vascular Smooth Muscle Cells

Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats.

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