Saha Cardiovascular Research Center, BBSRB, Room B243, University of Kentucky, Lexington, KY 40536-0509, USA.
Circ Res. 2010 Oct 15;107(8):953-8. doi: 10.1161/CIRCRESAHA.110.219089. Epub 2010 Aug 26.
Peroxisome proliferator-activated receptor (PPAR)γ agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPARγ, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs).
To determine whether a PPARγ agonist reduces angiotensin II (Ang II)-induced atherosclerosis and AAAs via interaction with SMC-specific PPARγ.
Low-density lipoprotein receptor (LDLR)(-/-) mice with SMC-specific PPARγ deficiency were developed using PPARγ floxed (PPARγ(f/f)) and SM22 Cre(+) mice. PPARγ(f/f) littermates were generated that did not express Cre (Cre(0/0)) or were hemizygous for Cre (Cre(+/0)). To assess the contribution of SMC-specific PPARγ in ligand-mediated attenuation of Ang II-induced atherosclerosis and AAAs, both male and female Cre(0/0) and Cre(+/0) mice were fed a fat-enriched diet with or without the PPARγ agonist pioglitazone (Pio) (20 mg/kg per day) for 5 weeks. After 1 week of feeding modified diets, mice were infused with Ang II (1000 ng/kg per minute) for 4 weeks. SMC-specific PPARγ deficiency or Pio administration had no effect on plasma cholesterol concentrations. Pio administration attenuated Ang II-increased systolic blood pressure equivalently in both Cre(0/0) and Cre(+/0) groups. SMC-specific PPARγ deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre(0/0) mice, but not in mice with SMC-specific PPARγ deficiency. SMC-specific PPARγ deficiency or Pio administration had no effect on Ang II-induced AAA development. Pio also did not attenuate Ang II-induced monocyte chemoattractant protein-1 production in PPARγ-deficient SMCs.
Pio attenuates Ang II-induced atherosclerosis via the interaction with SMC-specific PPARγ, but has no effect on the development of AAAs.
过氧化物酶体增殖物激活受体 (PPAR)γ 激动剂可减轻动脉粥样硬化和腹主动脉瘤 (AAA)。PPARγ 是一种核受体，存在于包括平滑肌细胞 (SMCs) 在内的多种细胞类型中。
确定 PPARγ 激动剂是否通过与 SMC 特异性 PPARγ 相互作用来减少血管紧张素 II (Ang II) 诱导的动脉粥样硬化和 AAA。
使用 PPARγ 基因敲入 (PPARγ(f/f)) 和 SM22 Cre(+) 小鼠，开发了 SMC 特异性 PPARγ 缺陷的低密度脂蛋白受体 (LDLR)(-/-) 小鼠。生成了不表达 Cre(0/0) 或 Cre(+/0) 的 PPARγ(f/f) 同窝仔鼠。为了评估 SMC 特异性 PPARγ 在配体介导的 Ang II 诱导的动脉粥样硬化和 AAA 减轻中的作用，雄性和雌性 Cre(0/0) 和 Cre(+/0) 小鼠分别喂食富含脂肪的饮食，或喂食富含脂肪的饮食加或不加 PPARγ 激动剂吡格列酮 (Pio)(20mg/kg/天)，持续 5 周。在进行改良饮食喂养 1 周后，小鼠接受 Ang II(1000ng/kg/分钟)输注 4 周。SMCs 特异性 PPARγ 缺失或 Pio 给药对血浆胆固醇浓度没有影响。Pio 给药同样可减轻 Cre(0/0)和 Cre(+/0)两组 Ang II 引起的收缩压升高。SMCs 特异性 PPARγ 缺失增加了雄性小鼠的动脉粥样硬化。Pio 给药仅在 Cre(0/0)小鼠中减轻了动脉粥样硬化，但在 SMC 特异性 PPARγ 缺失的小鼠中没有作用。SMCs 特异性 PPARγ 缺失或 Pio 给药对 Ang II 诱导的 AAA 发展没有影响。Pio 也没有减轻 Ang II 诱导的 PPARγ 缺失的 SMCs 中单核细胞趋化蛋白-1 的产生。
Pio 通过与 SMC 特异性 PPARγ 相互作用减轻 Ang II 诱导的动脉粥样硬化，但对 AAA 的发展没有影响。
