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

Hypertension ◽  
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.

scholarly journals Effect of Salusin-ß on Peroxisome Proliferator-Activated Receptor Gamma Gene Expression in Vascular Smooth Muscle Cells and its Possible Mechanism

2015 ◽  
Vol 36 (6) ◽  
pp. 2466-2479 ◽  
Author(s):  
XiaoLe Xu ◽  
Mengzi He ◽  
Tingting Liu ◽  
Yi Zeng ◽  
Wei Zhang
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Nuclear Translocation ◽  
Muscle Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Gene

Background/Aims: salusin-ß is considered to be a potential pro-atherosclerotic factor. Regulation and function of vascular smooth muscle cells (VSMCs) are important in the progression of atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts a vascular protective role beyond its metabolic effects. Salusin-ß has direct effects on VSMCs. The aim of the present study was to assess the effect of salusin-ß on PPARγ gene expression in primary cultured rat VSMCs. Methods: Western blotting analysis, real-time PCR and transient transfection approach were used to determine expression of target proteins. Specific protein knockdown was performed with siRNA transfection. Cell proliferation was determined by 5-bromo-2'-deoxyuridine incorporation. The levels of inflammation indicators interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) were determined using enzyme-linked immunosorbent assay. Results: Salusin-ß negatively regulated PPARγ gene expression at protein, mRNA and gene promoter level in VSMCs. The inhibitory effect of salusin-ß on PPARγ gene expression contributed to salusin-ß-induced VSMCs proliferation and inflammation in vitro. IγBa-NF-γB activation, but not NF-γB p50 or p65, mediated the salusin-ß-induced inhibition of PPARγ gene expression. Salusin-ß induced nuclear translocation of histone deacetylase 3 (HDAC3). HDAC3 siRNA prevented salusin-ß-induced PPARγ reduction. Nuclear translocation of HDAC3 in response to salusin-ß was significantly reversed by an IγBa inhibitor BAY 11-7085. Furthermore, IγBa-HDAC3 complex was present in the cytosol of VSMCs but interrupted after salusin-ß treatment. Conclusion: IγBa-HDAC3 pathway may contribute to salusin-ß-induced inhibition of PPARγ gene expression in VSMCs.

scholarly journals Proliferation of Vascular Smooth Muscle Cells under ox-LDL Is Regulated by Alismatis rhizoma Decoction via InhibitingERK1/2 and miR-17∼92a Cluster Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Julian Shen ◽  
Wei Wei ◽  
Xialei Wang ◽  
Jingda Yang ◽  
Lu Lu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cyclin D1 ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Density Lipoprotein ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Vsmc Proliferation

Context: Alismatis rhizome decoction (AD) exhibits antiatherosclerotic activities. The activity of AD against vascular smooth muscle cell (VSMC) proliferation remains unclear. Objective. The mechanisms and effects of AD on oxidized low-density lipoprotein (ox-LDL)-induced VSMC proliferation were explored. Materials and methods. The male SD rats were fed with AD (2.56 g/mL) or 0.9% NaCl by oral gavage 4 mL twice daily for 7 d. Then, AD-containing serum (ADcs) was collected. MTS assay was applied to measure the VSMC viability. The proliferation of VSMCs was detected by 5-bromodeoxyuridine (BrdU) immunocytochemistry. The microRNA (miRNA) profiling was performed, and the target genes of miRNAs were searched from the TargetScan 7.2 database. The expressions of matrix metalloproteinases-2/9 (MMP-2/9), cyclin D1/E, cyclin-dependent kinase inhibitor 1B (p27), extracellular regulated protein kinases 1/2 (ERK1/2), and ERK1/2 phosphorylation were examined by western blotting or quantitative reverse transcription PCR. Results. The ox-LDL-induced miR-17-92a expression promoted VSMC proliferation. AD and the ERK1/2 inhibitor U0126 (10 μmol/L) inhibited VSMC proliferation and reduced the overexpression of miR-17∼92a. AD was found to inhibit phosphorylation of ERK1/2 and reduced the expression of MMP-2/9 in VSMCs. The expression of cyclin D1/E was suppressed, and p27 was elevated following treatment with AD as well as ERK1/2 inhibitor. According to the TargetScan 7.2 database, the target genes of miR-17∼92a act on tissue inhibitors of metalloproteinases (TIMPs)-MMPs, p27/21 cyclins, and peroxisome-proliferator-activated receptor α (PPARα) ATP-binding cassette transporter (ABC) A1/G1, which are involved in the process of atherosclerosis. Conclusions. AD inhibits ox-LDL-induced VSMC proliferation via inhibiting ERK1/2 and miR-17∼92a activation. The results provide the multitarget mechanisms for application of AD in the treatment of atherosclerosis. It would be helpful to the treatment of cardiovascular and cerebral diseases.

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