Abstract
Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated β galactosidase activity. The number of β galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases.
Highlights
The vascular endothelium is critical to preserve vascular homeostasis, which includes tonus regulation, barrier function, and anti-coagulation
Treatment with ABT737 almost completely attenuated β galactosidase positive cell populations in endothelial cells (ECs) induced by the Angiotensin II (AngII) stimulation (Figure 1D,E and Supplementary Figure S1a–c) supporting the specificity of the β galactosidase staining as a marker of senescent ECs
We have demonstrated that AngII induces mitochondrial fission and endoplasmic reticulum (ER) stress in ECs, contributing to EC senescence and pro-inflammatory phenotype (Figure 5)
Summary
The vascular endothelium is critical to preserve vascular homeostasis, which includes tonus regulation, barrier function, and anti-coagulation. Endothelial cells (ECs), which form the monolayer of vascular endothelium, are believed to protect against vascular pathology associated with hypertension as well as atherosclerosis, the two major causes for cardiovascular mortality [1,2]. Ample evidence suggests that the disruption of EC homeostasis, termed endothelial dysfunction, is the predominant driving force for the development of these diseases in human as well as established animal models [1,2,3]. The phenotype of endothelial dysfunction is characterized by reduced vasodilation, disruption in barrier integrity, oxidative stress, and enhanced inflammatory responses. Detailed molecular mechanisms causing the pro-inflammatory phenotype of the dysfunctional ECs are not fully explored, which hampers the development of specific medications to preserve endothelial function
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