Regulation of mitochondrial morphology by positive feedback interaction between PKCδ and Drp1 in vascular smooth muscle cell.
Dynamin-related protein-1 (Drp1) plays a critical role in mitochondrial fission which allows cell proliferation and Mdivi-1, a specific small molecule Drp1 inhibitor, is revealed to attenuate proliferation. However, few molecular mechanisms-related to Drp1 under stimulus for restenosis or atherosclerosis have been investigated in vascular smooth muscle cells (vSMCs). Therefore, we hypothesized that Drp1 inhibition can prevent vascular restenosis and investigated its regulatory mechanism. Angiotensin II (Ang II) or hydrogen peroxide (H2 O2 )-induced proliferation and migration in SMCs were attenuated by down-regulation of Drp1 Ser 616 phosphorylation, which was demonstrated by in vitro assays for migration and proliferation. Excessive amounts of ROS production and changes in mitochondrial membrane potential were prevented by Drp1 inhibition under Ang II and H2 O2 . Under the Ang II stimulation, activated Drp1 interacted with PKCδ and then activated MEK1/2-ERK1/2 signaling cascade and MMP2, but not MMP9. Furthermore, in ex vivo aortic ring assay, inhibition of the Drp1 had significant anti-proliferative and -migration effects for vSMCs. A formation of vascular neointima in response to a rat carotid artery balloon injury was prevented by Drp1 inhibition, which shows a beneficial effect of Drp1 regulation in the pathologic vascular condition. Drp1-mediated SMC proliferation and migration can be prevented by mitochondrial division inhibitor (Mdivi-1) in in vitro, ex vivo and in vivo, and these results suggest the possibility that Drp1 can be a new therapeutic target for restenosis or atherosclerosis.
Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
Soyeon
S
Lim
Se-Yeon
SY
Lee
Hyang-Hee
HH
Seo
Onju
O
Ham
Changyeon
C
Lee
Jun-Hee
JH
Park
Jiyun
J
Lee
Minji
M
Seung
Ina
I
Yun
Sun M
SM
Han
Seahyoung
S
Lee
Eunhyun
E
Choi
Ki-Chul
KC
Hwang
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058426:Neointima / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats
D000804:Angiotensin II; D006861:Hydrogen Peroxide; D051745:Protein Kinase C-delta; C486391:Dnm1l protein, mouse; D034281:Dynamins
Drp1; MIGRATION; NEOINTIMAL FORMATION; PKCδ; PROLIFERATION; VASCULAR SMOOTH MUSCLE CELL