Endothelial Senescence Contributes to Heart Failure With Preserved Ejection Fraction in an Aging Mouse Model
Endothelial Senescence Contributes to Heart Failure With Preserved Ejection Fraction in an Aging Mouse Model
复制标题
内皮细胞衰老导致老年小鼠射血分数保留性心力衰竭
DOI：
10.1161/circheartfailure.116.003806
复制
发表时间：
2017-06-01
影响因子：
9.7
通讯作者：
Van Craenenbroeck, Emeline M.
中科院分区：
文献类型：
--
作者：
Gevaert, Andreas B.;Shakeri, Hadis;Van Craenenbroeck, Emeline M.
背景-由于全球老龄化，射血分数保留性心力衰竭（HFpEF）的患病率持续上升。虽然HFpEF的病理生理学仍不完全清楚，内皮炎症据说发挥核心作用。细胞衰老是与衰老和炎症相关的细胞生长停滞的过程。我们用小鼠加速老化HFpEF development.Methods和结果衰老加速小鼠（SAM，n=18）和正常衰老的对照小鼠（n=15）的细胞衰老的作用进行了调查，喂养正常的食物或高脂肪，高盐饮食（WD）。在8、16和24周龄时评估血管和心脏功能。在24周时，SAM WD（SAM WD）和SAM常规饮食显示内皮功能障碍，乙酰胆碱诱导的主动脉段舒张受损和基础一氧化氮减少证明。在第24周，SAM-WD发生HFpEF，特征为舒张功能障碍、左心室肥大、左心房扩张和间质纤维化。此外，运动能力降低，肺重量增加。心血管炎症和衰老通过免疫组织化学和免疫荧光染色的心脏和动脉进行评估。SAM-WD显示内皮炎症增加（细胞间粘附分子1表达）和内皮衰老增加（乙酰-p53/CD 31共染色）。后者与舒张功能和细胞间粘附分子1表达相关。添加高盐、高脂肪饮食加速内皮衰老并引发内皮炎症。这与HFpEF典型的血流动力学和结构变化一致。靶向内皮衰老可能是HFpEF的一种新的治疗途径。
Background-Because of global aging, the prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise. Although HFpEF pathophysiology remains incompletely understood, endothelial inflammation is stated to play a central role. Cellular senescence is a process of cellular growth arrest linked with aging and inflammation. We used mice with accelerated aging to investigate the role of cellular senescence in HFpEF development.Methods and Results-Senescence-accelerated mice (SAM, n=18) and control mice with normal senescence (n=15) were fed normal chow or a high-fat, high-salt diet (WD). Vascular and cardiac function was assessed at 8, 16, and 24 weeks of age. At 24 weeks, both SAM on WD (SAM-WD) and SAM on regular diet displayed endothelial dysfunction, as evidenced by impaired acetylcholine-induced relaxation of aortic segments and reduced basal nitric oxide. At week 24, SAM-WD had developed HFpEF, characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, and interstitial fibrosis. Also, exercise capacity was reduced and lung weight increased. Cardiovascular inflammation and senescence were assessed by immunohistochemical and immunofluorescence staining of hearts and aortas. SAM-WD showed increased endothelial inflammation (intercellular adhesion molecule 1 expression) and increased endothelial senescence (acetyl-p53/CD31 costaining). The latter correlated with diastolic function and intercellular adhesion molecule 1 expression.Conclusions-SAM develop endothelial dysfunction. Adding a high-salt, high-fat diet accelerates endothelial senescence and instigates endothelial inflammation. This coincides with hemodynamic and structural changes typical of HFpEF. Targeting endothelial senescence could be a new therapeutic avenue in HFpEF.