Dataset Information

Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-? Disrupts Vascular Wall Structure and Function.

ABSTRACT: Activation of the nuclear hormone receptor, PPAR?, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPAR?-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPAR? in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPAR? overexpression (smPPAR?OE). Our results demonstrate that smPPAR?OE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPAR?OE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPAR? overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPAR? overexpression disrupts vascular wall structure and function, emphasizing that balanced PPAR? activity is essential for vascular smooth muscle homeostasis.

SUBMITTER: Kleinhenz JM

PROVIDER: S-EPMC4599849 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function.

Kleinhenz Jennifer M JM Murphy Tamara C TC Pokutta-Paskaleva Anastassia P AP Gleason Rudolph L RL Lyle Alicia N AN Taylor W Robert WR Blount Mitsi A MA Cheng Juan J Yang Qinglin Q Sutliff Roy L RL Hart C Michael CM

PloS one 20151009 10

Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structur ...[more]

PMID: 26451838

Similar Datasets

Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-? Disrupts Vascular Wall Structure and Function.

Publications

Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets