Involvement of Senescence and Mitochondrial Fission in Endothelial Cell Pro-Inflammatory Phenotype Induced by Angiotensin II
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.
ER stress, angiotensin II, endothelial cells, inflammation, senolytic
Medical Subject Headings
Angiotensin II (pharmacology); Animals; Biphenyl Compounds (pharmacology); Cell Adhesion (drug effects); Cells, Cultured; Cellular Senescence (drug effects); Endoplasmic Reticulum Stress (drug effects); Endothelial Cells (cytology, metabolism); Humans; Mitochondria (drug effects, metabolism); Mitochondrial Dynamics (drug effects); Monocytes (cytology, drug effects); Nitrophenols (pharmacology); Phenotype; Phenylbutyrates (pharmacology); Piperazines (pharmacology); Proteostasis; Rats; Sulfonamides (pharmacology); THP-1 Cells
International journal of molecular sciences
Digital Object Identifier (DOI)
Miyao, Masashi; Cicalese, Stephanie; Kawai, Tatsuo; Cooper, Hannah A.; Boyer, Michael J.; Elliott, Katherine J.; Forrester, Steven J.; Kuroda, Ryohei; Rizzo, Victor; Hashimoto, Tomoki; Scalia, Rosario; and Eguchi, Satoru, "Involvement of Senescence and Mitochondrial Fission in Endothelial Cell Pro-Inflammatory Phenotype Induced by Angiotensin II" (2020). Translational Neuroscience. 1682.