Abelanet Alice, Camoin Marion, Rubin Sebastien, Bougaran Pauline, Delobel Valentin, Pernot Mathieu, Forfar Isabelle, Guilbeau-Frugier Céline, Galès Céline, Bats Marie Lise, Renault Marie-Ange, Dufourcq Pascale, Couffinhal Thierry, Duplàa Cécile
University of Bordeaux, INSERM, Biologie des maladies cardiovasculaires, U1034, Pessac, France (A.A., M.C., S.R., P.B., V.D., M.P., I.F., M.L.B., M.-A.R., P.D., T.C., C.D.).
CHU de Bordeaux, Pessac, France (M.C., S.R., M.P., M.L.B., P.D., T.C.).
Arterioscler Thromb Vasc Biol. 2022 Jun;42(6):745-763. doi: 10.1161/ATVBAHA.121.317319. Epub 2022 May 5.
While endothelial dysfunction is suggested to contribute to heart failure with preserved ejection fraction pathophysiology, understanding the importance of the endothelium alone, in the pathogenesis of diastolic abnormalities has not yet been fully elucidated. Here, we investigated the consequences of specific endothelial dysfunction on cardiac function, independently of any comorbidity or risk factor (diabetes or obesity) and their potential effect on cardiomyocyte.
The ubiquitine ligase , expressed in endothelial cells (ECs), was shown to destabilize tight junction. A genetic mouse model in which is overexpressed in EC (iEC-Pdzrn3) in adults was developed.
EC-specific expression increased cardiac leakage of IgG and fibrinogen blood-born molecules. The induced edema demonstrated features of diastolic dysfunction, with increased end-diastolic pressure, alteration of dP/dt min, increased natriuretic peptides, in addition to limited exercise capacity, without major signs of cardiac fibrosis and inflammation. Electron microscopic images showed edema with disrupted EC-cardiomyocyte interactions. RNA sequencing analysis of gene expression in cardiac EC demonstrated a decrease in genes coding for endothelial extracellular matrix proteins, which could be related to the fragile blood vessel phenotype. Irregularly shaped capillaries with hemorrhages were found in heart sections of iEC- mice. We also found that a high-fat diet was not sufficient to provoke diastolic dysfunction; high-fat diet aggravated cardiac inflammation, associated with an altered cardiac metabolic signature in EC- mice, reminiscent of heart failure with preserved ejection fraction features.
An increase of endothelial permeability is responsible for mediating diastolic dysfunction pathophysiology and for aggravating detrimental effects of a high-fat diet on cardiac inflammation and metabolism.
虽然内皮功能障碍被认为与射血分数保留的心力衰竭病理生理学有关，但仅了解内皮在舒张功能异常发病机制中的重要性尚未完全阐明。在此，我们研究了特定内皮功能障碍对心脏功能的影响，独立于任何合并症或危险因素（糖尿病或肥胖）及其对心肌细胞的潜在影响。
在内皮细胞（ECs）中表达的泛素连接酶被证明会破坏紧密连接。构建了一种成年期EC中过表达（iEC-Pdzrn3）的基因小鼠模型。
EC特异性表达增加了IgG和纤维蛋白原等血液中分子的心脏渗漏。诱导的水肿表现出舒张功能障碍的特征，舒张末期压力增加、dP/dt min改变、利钠肽增加，此外运动能力受限，且无明显的心脏纤维化和炎症迹象。电子显微镜图像显示水肿伴有EC-心肌细胞相互作用的破坏。对心脏EC中基因表达的RNA测序分析表明，编码内皮细胞外基质蛋白的基因减少，这可能与脆弱的血管表型有关。在iEC-小鼠的心脏切片中发现了形状不规则且有出血的毛细血管。我们还发现高脂饮食不足以引发舒张功能障碍；高脂饮食加重了心脏炎症，与EC-小鼠心脏代谢特征改变有关，类似于射血分数保留的心力衰竭特征。
内皮通透性增加是介导舒张功能障碍病理生理学以及加重高脂饮食对心脏炎症和代谢有害影响的原因。
