TY - JOUR
T1 - Macrophage (drp1) dynamin-related protein 1 accelerates intimal thickening after vascular injury
AU - Umezu, Ryuta
AU - Koga, Junichiro
AU - Matoba, Tetsuya
AU - Katsuki, Shunsuke
AU - Wang, Lixiang
AU - Hasuzawa, Nao
AU - Nomura, Masatoshi
AU - Tsutsui, Hiroyuki
AU - Egashira, Kensuke
N1 - Funding Information:
This research was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Tokyo, Japan (17K16011 and 19K08518 to J. Koga and 17K09590 to T. Matoba) and Intractable Diseases Overcome Research Project from the Japan Agency for Medical Research and Development (AMED to K. Egashira).
Publisher Copyright:
© 2020 American Heart Association, Inc.
PY - 2020/7
Y1 - 2020/7
N2 - Objective: Mitochondria consistently change their morphology in a process regulated by proteins, including Drp1 (dynaminrelated protein 1), a protein promoting mitochondrial fission. Drp1 is involved in the mechanisms underlying various cardiovascular diseases, such as myocardial ischemia/reperfusion injury, heart failure, and pulmonary arterial hypertension. However, its role in macrophages, which promote various vascular diseases, is poorly understood. We therefore tested our hypothesis that macrophage Drp1 promotes vascular remodeling after injury. Method and Results: To explore the selective role of macrophage Drp1, we created macrophage-selective Drp1-deficient mice and performed femoral arterial wire injury. In these mice, intimal thickening and negative remodeling were attenuated at 4 weeks after injury when compared with control mice. Deletion of macrophage Drp1 also attenuated the macrophage accumulation and cell proliferation in the injured arteries. Gain- and loss-of-function experiments using cultured macrophages indicated that Drp1 induces the expression of molecules associated with inflammatory macrophages. Morphologically, mitochondrial fission was induced in inflammatory macrophages, whereas mitochondrial fusion was induced in less inflammatory/reparative macrophages. Pharmacological inhibition or knockdown of Drp1 decreased the mitochondrial reactive oxygen species and chemotactic activity in cultured macrophages. Co-culture experiments of macrophages with vascular smooth muscle cells indicated that deletion of macrophage Drp1 suppresses growth and migration of vascular smooth muscle cells induced by macrophage-derived soluble factors. Conclusions: Macrophage Drp1 accelerates intimal thickening after vascular injury by promoting macrophage-mediated inflammation. Macrophage Drp1 may be a potential therapeutic target of vascular diseases.
AB - Objective: Mitochondria consistently change their morphology in a process regulated by proteins, including Drp1 (dynaminrelated protein 1), a protein promoting mitochondrial fission. Drp1 is involved in the mechanisms underlying various cardiovascular diseases, such as myocardial ischemia/reperfusion injury, heart failure, and pulmonary arterial hypertension. However, its role in macrophages, which promote various vascular diseases, is poorly understood. We therefore tested our hypothesis that macrophage Drp1 promotes vascular remodeling after injury. Method and Results: To explore the selective role of macrophage Drp1, we created macrophage-selective Drp1-deficient mice and performed femoral arterial wire injury. In these mice, intimal thickening and negative remodeling were attenuated at 4 weeks after injury when compared with control mice. Deletion of macrophage Drp1 also attenuated the macrophage accumulation and cell proliferation in the injured arteries. Gain- and loss-of-function experiments using cultured macrophages indicated that Drp1 induces the expression of molecules associated with inflammatory macrophages. Morphologically, mitochondrial fission was induced in inflammatory macrophages, whereas mitochondrial fusion was induced in less inflammatory/reparative macrophages. Pharmacological inhibition or knockdown of Drp1 decreased the mitochondrial reactive oxygen species and chemotactic activity in cultured macrophages. Co-culture experiments of macrophages with vascular smooth muscle cells indicated that deletion of macrophage Drp1 suppresses growth and migration of vascular smooth muscle cells induced by macrophage-derived soluble factors. Conclusions: Macrophage Drp1 accelerates intimal thickening after vascular injury by promoting macrophage-mediated inflammation. Macrophage Drp1 may be a potential therapeutic target of vascular diseases.
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U2 - 10.1161/ATVBAHA.120.314383
DO - 10.1161/ATVBAHA.120.314383
M3 - Article
C2 - 32493171
AN - SCOPUS:85087655709
VL - 40
SP - E214-E226
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 7
ER -