T-cell senescence accelerates angiotensin II-induced target organ damage

• Published in: Cardiovascular research Vol. 117; no. 1; pp. 271 - 283
• Main Authors: Pan, Xiao-Xi, Wu, Fang, Chen, Xiao-Hui, Chen, Dong-Rui, Chen, Hong-Jin, Kong, Ling-Ran, Ruan, Cheng-Chao, Gao, Ping-Jin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2021
• Subjects: Adoptive Transfer; Angiotensin II; Animals; Aorta - immunology; Aorta - metabolism; Aorta - pathology; Cardiovascular Diseases - immunology; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - pathology; Cell Line; Disease Models, Animal; Homeodomain Proteins - genetics; Humans; Hypertension - chemically induced; Hypertension - immunology; Hypertension - metabolism; Hypertension - pathology; Immunosenescence; Inflammation Mediators - metabolism; Interferon-gamma - genetics; Interferon-gamma - metabolism; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidney Diseases - immunology; Kidney Diseases - metabolism; Kidney Diseases - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium - immunology; Myocardium - metabolism; Myocardium - pathology; Oxidative Stress; Phenotype; Superoxides - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Time Factors; Cardiorenal dysfunction; Senescence; Angiotensin II; T cell
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvaa032

Abstract Aims Aging is a risk factor for cardiovascular diseases and adaptive immunity has been implicated in angiotensin (Ang) II-induced target organ dysfunction. Herein, we sought to determine the role of T-cell senescence in Ang II-induced target organ impairment and to explore the underlying mechanisms. Methods and results Flow cytometric analysis revealed that T cell derived from aged mice exhibited immunosenescence. Adoptive transfer of aged T cells to immunodeficient RAG1 KO mice accelerates Ang II-induced cardiovascular and renal fibrosis compared with young T-cell transfer. Aged T cells also promote inflammatory factor expression and superoxide production in these target organs. In vivo and in vitro studies revealed that Ang II promotes interferon-gamma (IFN-γ) production in the aged T cells comparing to young T cells. Importantly, transfer of senescent T cell that IFN-γ KO mitigates the impairment. Aged T-cell-conditioned medium stimulates inflammatory factor expression and oxidative stress in Ang II-treated renal epithelial cells compared with young T cells, and these effects of aged T-cell-conditioned medium are blunted after IFN-γ-neutralizing antibody pre-treatment. Conclusion These results provide a significant insight into the contribution of senescent T cells to Ang II-induced cardiovascular dysfunction and provide an attractive possibility that targeting T cell specifically might be a potential strategy to treat elderly hypertensive patients with end-organ dysfunction. Graphical Abstract