Vascular smooth muscle cell-specific progerin expression in a mouse model of Hutchinson-Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite
Vascular smooth muscle cell-specific progerin expression in a mouse model of Hutchinson-Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite
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DOI：
10.1111/acel.12936
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发表时间：
2019-06-01
期刊：
影响因子：
7.8
通讯作者：
Andres, Vicente
中科院分区：
文献类型：
--
作者：
del Campo, Lara;Sanchez-Lopez, Amanda;Andres, Vicente
血管僵硬是正常衰老过程中心血管疾病的主要原因，也是Hutchinson-Gilford早衰综合征（HGPS）的主要原因，HGPS是一种由普遍存在的早老蛋白表达引起的罕见遗传性疾病。核纤层蛋白A的这种突变形式导致与心血管改变相关的过早衰老，导致平均14.6岁的死亡。我们研究了具有普遍存在的早老蛋白表达的Lmna（G609 G/G609 G）小鼠中血管僵硬的潜在机制，并测试了亚硝酸盐治疗的效果。我们还培育了Lmna（LCS/LCS）Tie 2Cre（+/tg）和Lmna（LCS/LCS）SM 22 α Cre（+/tg）小鼠，它们分别在内皮细胞（EC）和血管平滑肌细胞（VSMC）中特异性表达早老蛋白，以确定每种细胞类型对血管病理学的特异性贡献。我们发现Lmna（G609 G/G609 G）和Lmna（LCS/LCS）SM 22 α Cre（+/tg）小鼠的动脉中存在血管僵硬和向内重构，但Lmna（LCS/LCS）Tie 2Cre（+/tg）小鼠的动脉中没有。结构改变，在progeroid小鼠的腹主动脉与平滑肌组织含量减少，胶原沉积增加，并减少横向波动的弹性蛋白层中的媒体。功能研究确定胶原蛋白（不像弹性蛋白和细胞骨架）是早衰小鼠主动脉僵硬的潜在原因。与此相一致，我们发现胶原蛋白III、IV、V和XII在早老性尿道炎的介质中沉积增加。血管僵硬和向内重塑在早衰症小鼠预防饮用水中添加亚硝酸钠。总之，Lmna（G609 G/G609 G）动脉表现出僵硬和向内重塑，主要是由于早老蛋白诱导的VSMC损伤，这导致中膜胶原沉积增加和弹性蛋白结构的继发性改变。亚硝酸盐治疗可预防早衰症的血管僵硬。
Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in Lmna(G609G/G609G) mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred Lmna(LCS/LCS)Tie2Cre(+/tg)and Lmna(LCS/LCS)SM22 alpha Cre(+/tg) mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of Lmna(G609G/G609G) and Lmna(LCS/LCS)SM22 alpha Cre(+/tg), but not in those from Lmna(LCS/LCS)Tie2Cre(+/tg)mice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, Lmna(G609G/G609G) arteries exhibit stiffness and inward remodeling, mainly due to progerin-induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria.