Dataset Information

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice (Ppara ^ΔSMC) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptosis induced by angiotensin (Ang) II and hydrogen peroxide, and increased the migration of Ang II-challenged cells.

SUBMITTER: Duan Y

PROVIDER: S-EPMC8339143 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

Duan Yan Y Qi Dan D Liu Ye Y Song Yanting Y Wang Xia X Jiao Shiyu S Li Huihua H Gonzalez Frank J FJ Qi Yongfen Y Xu Qingbo Q Du Jie J Qu Aijuan A

Biochemistry and biophysics reports 20210728

Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice (<i>Ppara</i> <sup>ΔSMC</sup>) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptos ...[more]

PMID: 34381883

Similar Datasets

Project description:ObjectivePeroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in the vasculature; however, the role of PPARγ in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPARγ in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPARγ-mediated signaling pathways that may prevent the development of AAA.MethodsWe determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPARγ knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.ResultsThere 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 PPARγ signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPARγ overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPARγ 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 PPARγ 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-α expression.ConclusionIn this study, we identify PPARγ as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPARγ in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPARγ activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Project description:AimsPeroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Pparγ gene in VSMC (smPparγ-/-) would exaggerate ET-1-induced vascular injury.Methods and resultseET-1, smPparγ-/- and eET-1/smPparγ-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparγ inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparγ-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparγ-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPparγ-/-. Mesenteric artery reactive oxygen species increased in smPparγ and were further enhanced in eET-1/smPparγ-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ and increased further in eET-1/smPparγ-/-. Spleen CD11b+ cells were increased in smPparγ-/- and further enhanced in eET-1/smPparγ-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPparγ-/- but not in eET-1/smPparγ-/-. Spleen T regulatory lymphocytes increased in smPparγ and decreased in eET-1, and decreased further in eET-1/smPparγ-/-.ConclusionVSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.

Dataset Information

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

Publications

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets