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

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.

• Authors: Jing Ye, Bin Que, Ying Huang, Yingzhong Lin, Jiangbin Chen, Ling Liu, Ying Shi, Yuan Wang, Menglong Wang, Tao Zeng, Zhen Wang, Haiying Hu, Yao Xu, Lei Shi, Di Ye, Jianfang Liu, Huimin Jiang, Jun Wan, Qingwei Ji
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 115 Issue 6 Pg. 1102-1113 (05 01 2019) ISSN: 1755-3245 [Electronic] England
• PMID: 30395167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected].

Chemical References

• Antihypertensive Agents
• IL12A protein, human
• Il12a protein, mouse
• Interleukin-12 Subunit p35
• Angiotensin II
• Interleukin-12

Topics

• Adult
• Aged
• Angiotensin II
• Animals
• Antihypertensive Agents (administration & dosage)
• Aorta (metabolism, pathology, physiopathology)
• Blood Pressure (drug effects)
• Case-Control Studies
• Cell Differentiation
• Cells, Cultured
• Disease Models, Animal
• Female
• Humans
• Hypertension (chemically induced, drug therapy, metabolism, physiopathology)
• Interleukin-12 (administration & dosage)
• Interleukin-12 Subunit p35 (blood, deficiency, genetics)
• Macrophages (metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Phenotype
• Signal Transduction
• Vasoconstriction
• Vasodilation