Center for Cardiovascular Research (CCR), Richard-Thoma-Laboratories for Arteriogenesis, Charité - Universitaetsmedizin Berlin, Berlin, Germany.
Acta Physiol (Oxf). 2014 Feb;210(2):354-68. doi: 10.1111/apha.12179. Epub 2013 Nov 29.
PPARγ stimulation improves cardiovascular (CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell (EC), monocyte and smooth muscle cell (SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth.
In a rat model of adaptive cerebral arteriogenesis (3-VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg(-1); 10 mg kg(-1) compared with metformin 62.2 mg kg(-1) or sitagliptin 6.34 mg kg(-1)) for 21 days or (iii) after adding pioglitazone to G-CSF (40 μg kg(-1) every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied.
PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity (CVRC controls: 12 ± 7%; pio low: -2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G-CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration.
Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G-CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients.
过氧化物酶体增殖物激活受体γ（PPARγ）刺激可改善心血管（CV）风险因素，但不能改善整体临床结局。PPARγ 激动剂会干扰内皮细胞（EC）、单核细胞和平滑肌细胞（SMC）的激活、功能和增殖，这些生理过程对动脉侧支生长（动脉生成）至关重要。因此，我们评估了 PPARγ 刺激对大脑适应性和治疗性侧支生长的影响。
在适应性大脑动脉生成（3-VO）的大鼠模型中，评估了侧支生长和功能（i）在对照组中，（ii）在 PPARγ 刺激（吡格列酮 2.8mg/kg；10mg/kg 与二甲双胍 62.2mg/kg 或西他列汀 6.34mg/kg 相比）21 天后，或（iii）在添加吡格列酮到粒细胞集落刺激因子（40μg/kg 每隔一天）以诱导治疗性动脉生成 1 周后。研究了吡格列酮对内皮和 SMC 形态和增殖、单核细胞激活和迁移的影响。
PPARγ 刺激可减少脑血管侧支生长和血流动力学储备能力（CVRC 对照组：12±7%；吡格列酮低剂量组：-2±9%；吡格列酮高剂量组：1±7%；二甲双胍组：9±13%；西他列汀组：11±12%），拮抗 G-CSF 诱导的治疗性动脉生成，并干扰 EC 激活、SMC 增殖、单核细胞激活和迁移。
药物性 PPARγ 刺激抑制了促动脉生成的 EC 激活、单核细胞功能、SMC 增殖，从而抑制了适应性和 G-CSF 诱导的大脑动脉生成。进一步的研究应评估这种作用是否是噻唑烷二酮类药物在患者中使用与心血管风险相关的基础。
