Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
CIBER de Enfermedades Cardiovasculares (CIBERCV), Spain.
Cells. 2020 Mar 8;9(3):656. doi: 10.3390/cells9030656.
Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined and mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.
心血管疾病（CVD）是全球主要的死亡原因，而衰老则是其主要的危险因素。在亨廷顿氏舞蹈症-早老症（HGPS）中，衰老的速度要快得多，HGPS 是一种由普遍表达一种名为早衰蛋白的突变蛋白引起的罕见遗传疾病。HGPS 患者在十几岁时就去世了，主要是由于心血管并发症。与年龄相关的 CVD 的主要原因是内皮功能障碍和血管张力失调；然而，它们对早衰蛋白诱导的 CVD 的贡献仍未得到充分描述。在本研究中，我们发现具有普遍表达早衰蛋白的早衰样小鼠同时表现出内皮功能障碍和严重的收缩功能障碍。为了评估特定血管细胞类型对这些异常的相对贡献，我们检查了 和 小鼠，它们分别特异性地在血管内皮细胞（ECs）和血管平滑肌细胞（VSMCs）中表达早衰蛋白。虽然在具有 VSMC 特异性表达早衰蛋白的小鼠中观察到血管收缩受损，但在将早衰蛋白表达限制在 VSMCs 或 ECs 中的小鼠中未观察到内皮功能障碍。饮食亚硝酸钠补充可改善早衰样小鼠的血管张力调节。我们的结果表明，VSMCs 是引起 HGPS 小鼠模型收缩功能障碍的主要细胞类型，而亚硝酸钠治疗可改善这种情况。
