Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
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DOI：
10.15252/emmm.201809736
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发表时间：
2019-04-01
影响因子：
11.1
通讯作者：
Andres, Vicente
中科院分区：
文献类型：
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作者：
Hamczyk, Magda R.;Villa-Bellosta, Ricardo;Andres, Vicente
Hutchinson-Gilford早衰综合征（HGPS）是一种罕见的遗传性疾病，由早老蛋白（一种突变型核纤层蛋白A变体）引起。HGPS患者表现出加速老化和过早死亡，通常死于动脉粥样硬化并发症。最近，我们证明，早老蛋白驱动的血管平滑肌细胞（VSMC）的损失加速动脉粥样硬化，导致载脂蛋白E缺陷小鼠过早死亡。然而，这一过程的分子机制仍然未知。使用转录组学的方法，我们确定在这里内质网应激（ER）和未折叠的蛋白反应的驱动程序VSMC死亡的HGPS表现出无处不在的和VSMC特异性早老蛋白表达的两个小鼠模型。这种应激途径在HGPS患者来源的细胞中也被激活。在两种早老症模型中，用化学分子伴侣靶向ER应激反应延迟了中膜VSMC损失并抑制了动脉粥样硬化，并延长了VSMC特异性模型的寿命。我们的研究结果确定了HGPS心血管疾病的潜在机制，可以在患者中作为目标。此外，这些发现可能有助于了解与VSMC死亡相关的其他血管疾病，并提供与未加工的有毒形式的核纤层蛋白A积累相关的衰老依赖性血管损伤的见解。
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin-driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E-deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC-specific progerin expression. This stress pathway was also activated in HGPS patient-derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC-specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging-dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.