Gevaert Andreas B, Shakeri Hadis, Leloup Arthur J, Van Hove Cor E, De Meyer Guido R Y, Vrints Christiaan J, Lemmens Katrien, Van Craenenbroeck Emeline M
From the Research Group Physiopharmacology (A.B.G., H.S., A.J.L., C.E.V.H., G.R.Y.D.M., K.L.), and Research Group Cardiovascular Diseases, Translational Pathophysiological Research (A.B.G., C.E.V.H., C.J.V., K.L., E.M.V.C.), University of Antwerp, Belgium; and Laboratory for Cellular and Molecular Cardiology and Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium (A.B.G., C.J.V., E.M.V.C.).
Circ Heart Fail. 2017 Jun;10(6). doi: 10.1161/CIRCHEARTFAILURE.116.003806.
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.
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.
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.
由于全球老龄化，射血分数保留的心力衰竭（HFpEF）患病率持续上升。尽管HFpEF的病理生理学仍未完全了解，但内皮炎症被认为起着核心作用。细胞衰老过程是与衰老和炎症相关的细胞生长停滞过程。我们使用加速衰老的小鼠来研究细胞衰老在HFpEF发生发展中的作用。
将衰老加速小鼠（SAM，n = 18）和正常衰老的对照小鼠（n = 15）喂以正常饲料或高脂高盐饮食（WD）。在8周、16周和24周龄时评估血管和心脏功能。在24周时，WD喂养的SAM（SAM-WD）和常规饮食喂养的SAM均出现内皮功能障碍，表现为乙酰胆碱诱导的主动脉段舒张受损和基础一氧化氮减少。在24周时，SAM-WD已发展为HFpEF，其特征为舒张功能障碍、左心室肥厚、左心房扩张和间质纤维化。此外，运动能力下降，肺重量增加。通过心脏和主动脉的免疫组织化学和免疫荧光染色评估心血管炎症和衰老。SAM-WD显示内皮炎症增加（细胞间黏附分子1表达）和内皮衰老增加（乙酰化p53/CD31共染色）。后者与舒张功能和细胞间黏附分子1表达相关。
SAM出现内皮功能障碍。添加高脂高盐饮食会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。针对内皮衰老可能是HFpEF的一种新治疗途径。
