Vascular senescence in progeria: role of endothelial dysfunction.
Vascular senescence in progeria: role of endothelial dysfunction.
复制标题
早衰症的血管衰老：内皮功能障碍的作用。
DOI：
10.1093/ehjopen/oeac047
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Cooke, John P
中科院分区：
文献类型：
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作者：
Xu, Qiu;Mojiri, Anahita;Boulahouache, Luay;Morales, Elisa;Walther, Brandon K;Cooke, John P
Hutchinson-Gilford早衰综合征（HGPS）是由LMNA基因突变引起的过早衰老病症，导致不可逆的法尼基化核纤层蛋白A蛋白：早老蛋白。HGPS的主要死亡原因是冠状动脉和动脉闭塞性疾病。在HGPS小鼠模型中，血管平滑肌细胞（VSMC）损失是主要的血管表现，这与老年患者中观察到的动脉闭塞性疾病不同。为了确定人类HGPS血管疾病的机制，我们从HGPS诱导的多能干细胞（iPSC）和对照iPSC分化出等基因内皮细胞（EC）和VSMC。HGPS-EC和HGPS-VSMC均表现出衰老的细胞标志，包括畸形核、增殖受损、β-半乳糖苷酶染色增加、端粒缩短、炎性细胞因子分泌上调、DNA损伤增加、异染色质丢失和改变的shelterin蛋白复合物（SPC）表达。然而，在分化后的相似天数，即使具有较低水平的早老蛋白，HGPS-EC也表现出更严重的衰老迹象，部分地由较高百分比的β-半乳糖苷酶阳性细胞、较短的端粒长度和更多的DNA损伤信号指示。我们观察到HGPS-EC中γH2A.X与RAP 1的结合增加，而TRF 2与核纤层蛋白A的结合减少，但在HGPS-VSMC中没有。γH2A.X在HGPS-EC中的表达高于HGPS-VSMCs，并且与更大的端粒缩短、受损的SPC相互作用和异染色质丢失相关。尽管早老蛋白表达对EC和VSMCs都有有害影响，但与HGPS-VSMCs相比，HGPS-EC中的功能障碍更大。这项研究表明，内皮靶向治疗可能是有用的HGPS患者。早衰内皮细胞和血管平滑肌细胞表型示意图。HGPS-EC和HGPS-VSMC均表现出增加的炎性细胞因子表达、受损的shelterin复合蛋白、缩短的端粒、增加的DNA损伤和更大的DNA可及性。然而，DNA可及性和端粒缩短在HGPS-EC中更为严重，这表明在早衰症动脉闭塞性疾病的发生和发展中起重要作用。
Hutchinson–Gilford progeria syndrome (HGPS) is a pre-mature aging disorder caused by the mutation of the LMNA gene leading to an irreversibly farnesylated lamin A protein: progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vascular smooth muscle cell (VSMC) loss is the primary vascular manifestation, which is different from the arterial occlusive disease seen in older patients. To identify the mechanisms of HGPS vascular disease in humans, we differentiated isogenic endothelial cells (ECs) and VSMCs from HGPS-induced pluripotent stem cells (iPSCs) and control-iPSCs. Both HGPS-ECs and HGPS-VSMCs manifested cellular hallmarks of aging, including dysmorphic nuclei, impaired proliferation, increased β-galactosidase staining, shortened telomeres, up-regulated secretion of inflammatory cytokines, increased DNA damage, loss of heterochromatin, and altered shelterin protein complex (SPC) expression. However, at similar days after differentiation, even with lower levels of progerin, HGPS-ECs manifested more severe signs of senescence, as indicated in part by a higher percentage of β-galactosidase positive cells, shorter telomere length, and more DNA damage signals. We observed increased γH2A.X binding to RAP1 and reduced TRF2 binding to lamin A in HGPS-ECs but not in HGPS-VSMCs. The expression of γH2A.X was greater in HGPS-ECs than in HGPS-VSMCs and is associated with greater telomere shortening, impaired SPC interactions, and loss of heterochromatin. Although progerin expression has a deleterious effect on both ECs and VSMCs, the dysfunction is greater in HGPS-ECs compared with HGPS-VSMCs. This study suggests that an endothelial-targeted therapy may be useful for HGPS patients. A schematic figure of phenotypes for progeria endothelial cells (ECs) and vascular smooth muscle cell (VSMCs). Both HGPS-ECs and HGPS-VSMCs exhibit increased inflammatory cytokine expression, impaired shelterin complex proteins, shortened telomeres, increased DNA damage, and greater DNA accessibility. However, DNA accessibility and telomere shortening are far more severe in HGPS-ECs, suggesting an important role in the initiation and progression of the arterial occlusive disease in progeria.