Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway
Dafeng Yang,
Stefan Haemmig,
Haoyang Zhou,
Daniel Pérez-Cremades,
Xinghui Sun,
Lei Chen,
Jie Li,
Jorge Haneo-Mejia,
Tianlun Yang,
Ivana Hollan,
Mark W Feinberg
Affiliations
Dafeng Yang
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
Stefan Haemmig
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Haoyang Zhou
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Daniel Pérez-Cremades
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Xinghui Sun
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Lei Chen
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
Jie Li
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Jorge Haneo-Mejia
Department of Pathology and Laboratory Medicine, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, United States
Tianlun Yang
Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China
Ivana Hollan
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Lillehammer Hospital for Rheumatic diseases, Lillehammer, Norway; Norwegian University of Science and Technology, Gjøvik, Norway
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.
