Myeloid GPSM1 regulates atherosclerosis progression by governing monocyte and macrophage activation and chemotaxis
Abstract
The activation of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes remain unclear. Here, we report that G-protein signaling modulator 1 (GPSM1) plays a critical role in atherogenesis. We found that GPSM1 expression in lesional macrophages was increased during atherosclerosis development both in mice and humans. Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces aortic inflammation in both Apoe −/− mice and an AAV-PCSK9 injection model. Conversely, myeloid-restricted overexpression of GPSM1 accelerates aortic inflammation and promotes atherosclerosis development in mice. Mechanistically, GPSM1 deficiency suppressed monocyte activation including chemotaxis and adhesion through inhibition of the p38/ERK MAPK pathway regulated by the cAMP/PKA/KLF4/PMP22 axis, thereby alleviating proinflammatory responses within atherosclerotic plaques. Blockade of PMP22 using siRNA-loaded liposomes protected GPSM1 overexpression mice from atherosclerosis. Furthermore, a small-molecule compound inhibiting GPSM1 function could suppress atherosclerosis in vivo. In conclusion, our findings establish that GPSM1 is a regulator of atherosclerosis development and targeting GPSM1 might be a promising therapy against atherosclerosis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Yuemei Zhang
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes
Yuxin Cao
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes
Yongxin Sun
Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University
Chenxia Zhou
Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine
Xiaorui Lyu
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes
Daixi Wang
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes
Jiangfei Zheng
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes
Yuxin Shu
Lijun Yao
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes
Rong Zhang
Department of Materials Science and Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong 999077, China
Jingyong Li
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Feng Jiang
State Key Laboratory of Integrated Optoelectronics, JLU Region, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. China
Xiang Cheng
Jing Yan
Cheng Hu