Interleukin-12p35 knockout promotes macrophage differentiation, aggravates vascular dysfunction, and elevates blood pressure in angiotensin II-infused mice

• Published in: Cardiovascular research Vol. 115; no. 6; pp. 1102 - 1113
• Main Authors: Ye, Jing, Que, Bin, Huang, Ying, Lin, Yingzhong, Chen, Jiangbin, Liu, Ling, Shi, Ying, Wang, Yuan, Wang, Menglong, Zeng, Tao, Wang, Zhen, Hu, Haiying, Xu, Yao, Shi, Lei, Ye, Di, Liu, Jianfang, Jiang, Huimin, Wan, Jun, Ji, Qingwei
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.05.2019
• Subjects: Adult; Aged; Angiotensin II; Animals; Antihypertensive Agents - administration & dosage; Aorta - metabolism; Aorta - pathology; Aorta - physiopathology; Blood Pressure - drug effects; Case-Control Studies; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Female; Humans; Hypertension - chemically induced; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - physiopathology; Interleukin-12 - administration & dosage; Interleukin-12 Subunit p35 - blood; Interleukin-12 Subunit p35 - deficiency; Interleukin-12 Subunit p35 - genetics; Macrophages - metabolism; Macrophages - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Phenotype; Signal Transduction; Vasoconstriction; Vasodilation; Hypertension; Inflammatory response; Interleukin 12; Interleukin-12p35 deficiency; Angiotensin II; Macrophages
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvy263

Abstract Aims Numerous studies have demonstrated that inflammation is involved in the progression of hypertension. Inflammatory cytokines interleukin (IL)-12 and IL-35 belong to the IL-12 cytokine family and share the same IL-12p35 subunit. Accumulating evidence has demonstrated that IL-12p35 knockout (IL-12p35 KO) leads to cardiovascular disease by regulating the inflammatory response. This study aimed to investigate whether IL-12p35 KO elevates blood pressure in a hypertension mouse model. Methods and results Mice with angiotensin (Ang) II infusion showed marked aortic IL-12p35 expression; thus, aortic macrophages may be the main source of IL-12p35. Wild-type and IL-12p35 KO mice were infused with Ang II or saline. IL-12p35 KO promoted M1 macrophage differentiation, amplified the inflammatory response, aggravated vascular dysfunction, and elevated blood pressure in Ang II-treated mice. Then, some Ang II-infused mice were given phosphate buffer saline, mouse recombinant IL-12 (rIL-12), or rIL-35, and the results showed that rIL-12 but not rIL-35 treatment had an antihypertensive effect on Ang II-infused mice. In addition, detection of human plasma IL-12 levels in hypertensive patients and control subjects showed that IL-12 was significantly increased in hypertensive patients when compared with control subjects. In hypertensive patients, IL-12 levels were positively correlated with blood pressure. Conclusion IL-12p35 KO amplifies the inflammatory response and promotes blood pressure elevation in Ang II-treated mice. In addition, IL-12, but not IL-35, plays a protective role in the Ang II-induced hypertension model. Thus, IL-12 may be a novel therapeutic agent for the prevention and treatment of clinical hypertension.