Title

Involvement of Senescence and Mitochondrial Fission in Endothelial Cell Pro-Inflammatory Phenotype Induced by Angiotensin II

Authors

Masashi Miyao, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Stephanie Cicalese, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Tatsuo Kawai, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Hannah A. Cooper, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Michael J. Boyer, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Katherine J. Elliott, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Steven J. Forrester, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Ryohei Kuroda, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Victor Rizzo, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Tomoki Hashimoto, Department of Neurosurgery and Neurobiology, Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.Follow
Rosario Scalia, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Satoru Eguchi, Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.

Document Type

Article

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.

Keywords

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

Publication Date

4-28-2020

Publication Title

International journal of molecular sciences

E-ISSN

1422-0067

Volume

21

Issue

9

PubMed ID

32354103

Digital Object Identifier (DOI)

10.3390/ijms21093112

Share

COinS