1. Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway
- Author
-
Jie Li, Tianlun Yang, Dafeng Yang, Mark W. Feinberg, Stefan Haemmig, Daniel Pérez-Cremades, Jorge Haneo-Mejia, Xinghui Sun, Lei Chen, Ivana Hollan, and Haoyang Zhou
- Subjects
0301 basic medicine ,Male ,Adenosine ,medicine ,Mouse ,White adipose tissue ,030204 cardiovascular system & hematology ,Pharmacology ,Cardiovascular ,Pathogenesis ,Arthritis, Rheumatoid ,immunology ,Mice ,0302 clinical medicine ,Immunology and Inflammation ,Rheumatoid ,2.1 Biological and endogenous factors ,Biology (General) ,Aetiology ,Receptor ,microRNA ,General Neuroscience ,General Medicine ,endothelial cells ,3. Good health ,Endothelial stem cell ,Infectious Diseases ,adenosine ,5.1 Pharmaceuticals ,Antirheumatic Agents ,Medicine ,Female ,Stem Cell Research - Nonembryonic - Non-Human ,medicine.symptom ,Development of treatments and therapeutic interventions ,medicine.drug ,Research Article ,Human ,Signal Transduction ,QH301-705.5 ,Science ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,methotrexate ,03 medical and health sciences ,Insulin resistance ,Animals ,Humans ,human ,mouse ,Nutrition ,General Immunology and Microbiology ,business.industry ,Arthritis ,Inflammatory and immune system ,medicine.disease ,Stem Cell Research ,MicroRNAs ,030104 developmental biology ,inflammation ,Biochemistry and Cell Biology ,business - Abstract
Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (Mir181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating Mir181b expression. Both systemic and endothelial-specific Mir181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a Mir181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-Mir181b signaling cascade. These findings establish an essential role of endothelial Mir181b in controlling vascular inflammation and that restoring Mir181b in ECs by high-dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.
- Published
- 2021