LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial Hypertension That Is Reversed by PPARγ Activation
LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial Hypertension That Is Reversed by PPARγ Activation
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DOI：
10.1161/circresaha.119.315088
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发表时间：
2019-06-07
影响因子：
20.1
通讯作者：
Hansmann, Georg
中科院分区：
文献类型：
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作者：
Calvier, Laurent;Boucher, Philippe;Hansmann, Georg
理论基础：动脉重塑——包括肺动脉高压（PAH）在内的许多心血管疾病的标志——是由TGF β 1（转化生长因子- β 1）-TGF β受体和拮抗、血管保护性BMPR2（骨形态发生蛋白受体2）-PPAR γ（过氧化物酶体增殖物激活受体- γ）轴调控的。然而，目前尚不清楚哪些因素驱动高血压肺血管中有害的TGF β 1通路。目的：我们假设LRP1（低密度脂蛋白受体相关蛋白1）在PAH中表达降低，导致TGF β 1信号增强（去抑制），PPAR γ激动剂吡格列酮可以恢复血管稳态，防止血管平滑肌细胞（SMCs）中LRP1缺失导致的PAH。方法和结果：小鼠血管SMC中LRP1的靶向缺失（smLRP1(-/-)）去抑制TGF β 1-CTGF（结缔组织生长因子）信号，导致自发性PAH和远端肺动脉肌肉化，通过闭胸心导管穿刺和抗α SMA染色评估。吡格列酮抑制人肺动脉SMC和smLRP1（-/-）肺动脉主干（CTGF和NOX4）的典型TGF β 1-CTGF轴，逆转smLRP1（-/-）小鼠的PAH。与对照组相比，TGF β 1提高了smLRP1（-/-）小鼠PASMC中的pSmad3。吡格列酮激活的PPAR γ在人肺动脉SMC中与Smad3结合（共免疫沉淀），从而阻断其磷酸化并克服LRP1缺陷。最后，LRP1 mRNA和蛋白表达在终末期特发性PAH患者肺丛状病变中降低（激光捕获显微解剖、qPCR和免疫组织化学）。PAH患者外植的PASMC中也显示LRP1蛋白下调，并伴有TGF β 1-pSmad3-CTGF信号传导增强，TGF β 1诱导的PASMC增殖增加，吡格列酮可以阻止这种增殖。结论：在这里，我们发现LRP1是TGF β 1介导的调节小鼠血管重塑机制的整合子，临床PAH和PPAR γ是控制典型TGF β 1途径的治疗靶点。因此，药理学PPAR γ激活对于血管SMC中缺乏血管保护性LRP1的PAH患者来说是一种很有前景的新疗法。
Rationale: Arterial remodeling-a hallmark of many cardiovascular pathologies including pulmonary arterial hypertension (PAH)-is regulated by TGF beta 1 (transforming growth factor-beta 1)-TGF beta receptors and the antagonistic, vasoprotective BMPR2 (bone morphogenetic protein receptor 2)-PPAR gamma (peroxisome proliferator-activated receptor-gamma) axis. However, it is unclear which factors drive detrimental TGF beta 1 pathways in the hypertensive pulmonary vasculature. Objective: We hypothesized that LRP1 (low-density lipoprotein receptor-related protein 1) expression is decreased in PAH, leading to enhancement (disinhibition) of TGF beta 1 signals and that the PPAR gamma agonist pioglitazone can restore vascular homeostasis and prevent PAH resulting from LRP1 deletion in vascular smooth muscle cells (SMCs). Methods and Results: Targeted deletion of LRP1 in vascular SMC (smLRP1(-/-)) in mice disinhibited TGF beta 1-CTGF (connective tissue growth factor) signaling, leading to spontaneous PAH and distal pulmonary arterial muscularization as assessed by closed-chest cardiac catheterization and anti-alpha SMA staining. Pioglitazone inhibited the canonical TGF beta 1-CTGF axis in human pulmonary artery SMC and smLRP1(-/-) main pulmonary artery (CTGF and NOX4) and reversed PAH in smLRP1(-/-) mice. TGF beta 1 boosted pSmad3 in PASMC from smLRP1(-/-) mice versus controls. Pioglitazone-activated PPAR gamma binds to Smad3 in human pulmonary artery SMC (coimmunoprecipitation), thereby blocking its phosphorylation and overriding LRP1 deficiency. Finally, mRNA and protein expression of LRP1 was decreased in pulmonary plexiform lesions of patients with end-stage idiopathic PAH (laser capture microdissection, qPCR, and immunohistochemistry). Downregulation of LRP1 protein was also demonstrated in explanted PASMC from patients with PAH and accompanied by enhanced TGF beta 1-pSmad3-CTGF signaling and increased TGF beta 1-induced PASMC proliferation that was prevented by pioglitazone. Conclusions: Here, we identify LRP1 as an integrator of TGF beta 1-mediated mechanisms that regulate vascular remodeling in mice and clinical PAH and PPAR gamma as a therapeutic target that controls canonical TGF beta 1 pathways. Hence, pharmacologic PPAR gamma activation represents a promising new therapy for patients with PAH who lack the vasoprotective LRP1 in vascular SMC.