396 ANGIOTENSIN (ANG) TYPE 2 RECEPTOR (AT2R) REGULATES AORTIC SMOOTH MUSCLE CELL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR GAMMA) EXPRESSION IN VIVO IN APOLIPOPROTEIN (APO) E-DEFICIENT MICE

The study aimed to identify new nuclear cofactors for PPARgamma (peroxisome proliferator-activated receptor gamma)-dependent gene transcription in human aortic smooth muscle cells (HASMC) in order to develop new PPARgamma-ligands with improved clinical safety in the absence of deleterious cardiovascular side effects. Using an Oligo GEArray® Human Nuclear Receptors and Coregulators Microarray for gene expression profiling, we identified the transcriptional regulator and chromatin modifying High Mobility Group (HMG) A1 protein highly expressed in unstimulated HASMC. PPARgamma-dependent gene regulation was studied by analysis of PMA-induced MMP-9 (matrix metalloproteinase 9) expression ± pioglitazone (pio 10μM). PMA (50ng/ml) stimulated MMP-9 mRNA expression by 46.3±22.3-fold (p<0.05 vs. vehicle) which was markedly blocked by pio (10μM: 17.4±4.8-fold vs. PMA alone p<0.05). Pio also blocked PMA-induced MMP-9 promoter activity by 45% in transactivation assays in HEK293 using a pGL3-MMP-9 2.2 kb construct. To evaluate the role of HMGA1, gene silencing experiments with siRNA for HMGA1 were performed (91 % in HASMC and 80.2% in HEK293 reduction of HMGA1 protein expression). HMGA1 siRNA completely abolished PPARgamma-mediated MMP9-mRNA repression (control siRNA: pio-mediated MMP-9 regulation vs. PMA alone: −66.8 % in HASMC and −59.3% in HEK293 p<0.01; HMGA1 siRNA: pio-mediated MMP-9 regulation vs. PMA alone: +10.7 % in HASMC and +14.7% in HEK293 vs. PMA alone; p=n.s.). Knockdown of HMGA1 expression reverse trans-repression of MMP9 by PPARgamma in HASMCs. By using ChIP assay we could demonstrate that pio-induced PPARgamma activation leads to a potent recruitment of PPARgamma (3.0 fold vs.1.15 fold PMA alone) and HMGA1 complexes (1.24 fold vs. 0.0 fold PMA alone) to the MMP9 promoter in HASMC. In consonance with reduced promoter activity, RNA-Polymerase II was removed from the MMP9 promoter by pio (0.08 fold vs 1.04 fold PMA alone). In conclusion, HMGA1 is required for PPARgamma-mediated repression of MMP-9 gene transcription. Ligand-induced HMGA1-PPARgamma interactions might be an important determinant for ligand-specific anti-atherosclerotic actions.

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Abstract P224: Endothelin-1 Overexpression Preserves Endothelial Function in Mice with Vascular Smooth Muscle Cell-specific Deletion of PPAR-gamma

Hypertension ◽

10.1161/hyp.68.suppl_1.p224 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Sofiane Ouerd ◽

Noureddine Idris-Khodja ◽

Michelle Trindade ◽

Jordan Gornitsky ◽

Asia Rehman ◽

...

Keyword(s):

Oxidative Stress ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Endothelial Function ◽

T Regulatory Cells ◽

Ppar Gamma ◽

Reduce Blood Pressure ◽

Vascular Damage ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Objective: Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure (BP) and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) using a tamoxifen inducible Cre-Lox system enhanced angiotensin II-induced vascular damage. Transgenic mice overexpressing endothelin (ET)-1 in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar gene in VSMC (sm Pparγ -/- ) would exaggerate ET-1-induced vascular damage. Methods and Results: Eleven-week-old male control, eET-1, sm Pparγ -/- and eET-1/sm Pparγ -/- mice were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and sacrificed 4 weeks later. Systolic BP determined by telemetry was higher in eET-1 (123±5 vs 109±2 mm Hg, P <0.05) and unaffected by sm Pparγ inactivation. Mesenteric artery (MA) vasorelaxation to acetylcholine was impaired only in sm Pparγ -/- (E max : 52.0±6.7 vs 82.2±4.9%, P <0.05). MA reactive oxygen species levels were increased 1.7±0.3-fold in sm Pparγ -/- ( P <0.05) and further increased in eET-1/sm Pparγ -/- (2.5±0.3-fold, P <0.05). MA perivascular fat monocyte/macrophage infiltration was higher in eET-1 and sm Pparγ -/- (331±34 and 326±49 vs 140±8 cells/mm 2 , P <0.05), and further increased in eET-1/sm Pparγ -/- (557±77, P <0.05). The spleen fraction of CD11b + cells was increased in sm Pparγ -/- (1.1±0.1 vs 0.47±0.1%, P <0.05) and further increased in eET-1/sm Pparγ -/- (1.8±0.2%, P <0.05). The spleen fraction of Ly-6C hi monocytes was increased in eET-1 and sm Pparγ -/- (24±3 and 27±4 vs 14±1%, P <0.05) but not in eET-1/sm Pparγ -/- . The spleen fraction of T regulatory cells was increased in sm Pparγ -/- (13±2 vs 9±1%, P <0.05) and decreased in eET-1 (7±1%, P <0.05), which was further decreased by eET-1/sm Pparγ -/- (3±1%, P <0.05). Conclusions: These results suggest that increased ET-1 paradoxically preserves endothelial function in mice with inactivated VSMC Pparγ despite enhanced oxidative stress. Flow cytometry data indicate that infiltrating monocyte/macrophages in these mice might be anti-inflammatory.

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2-Hydroxy-4ʼ-Methoxychalcone Inhibits Proliferation and Inflammation of Human Aortic Smooth Muscle Cells by Increasing the Expression of Peroxisome Proliferator–Activated Receptor Gamma

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0b013e3182440486 ◽

2012 ◽

Vol 59 (4) ◽

pp. 339-351 ◽

Cited By ~ 12

Author(s):

Chin-San Liu ◽

Chen-Chia Chang ◽

Ying-Chi Du ◽

Fang-Rong Chang ◽

Yang-Chang Wu ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Aortic Smooth Muscle Cells ◽

Aortic Smooth Muscle

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Pioglitazone in the Treatment of Type 2 Diabetes: Safety and Efficacy Review

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.4137/cmed.s5372 ◽

2010 ◽

Vol 3 ◽

pp. CMED.S5372 ◽

Cited By ~ 3

Author(s):

Cyrus V. Desouza ◽

Vijay Shivaswamy

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Ppar Gamma ◽

New Drugs ◽

Peroxisome Proliferator ◽

Cardiovascular Safety ◽

Peroxisome Proliferator Activated Receptor ◽

Safety And Efficacy ◽

Beneficial Effects

The increase in obesity and the aging of the population has lead to an increase in the incidence of type 2 diabetes. This has led to the development of new drugs such as thiazolidinediones (TZDs) which are Peroxisome Proliferator-Activated Receptor (PPAR-gamma) agonists, to treat type 2 diabetes. TZDs have recently been at the center of a controversy with regards to their cardiovascular safety. Pioglitazone is a TZD which has been shown to be effective in glycemic control by lowering insulin resistance. Pioglitazone also has beneficial effects on lipid metabolism and cardiovascular risk. The safety and efficacy of pioglitazone including its pleotropic effects are discussed at length in this article.

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