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Inhibition of nitric oxide synthase transforms carotid occlusion-mediated benign oligemia into de novo large cerebral infarction

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Authors

Kim, Ha; Chung, Jinyong; Kang, Jeong Wook; Schellingerhout, Dawid; Lee, Soo Ji; Jang, Hee Jeong; Park, Inyeong; Kim, Taesu; Gwak, Dong-Seok; Lee, Ji Sung; Hong, Sung-Ha; Je, Kang-Hoon; Bae, Hee-Joon; Sung, Joohon; Lo, Eng H.; Faber, James; Ayata, Cenk; Kim, Dong-Eog

Issue Date
2025
Publisher
Ivyspring International Publisher
Citation
Theranostics, Vol.15 No.2, pp.585-604
Abstract
Rationale: It remains unclear why unilateral proximal carotid artery occlusion (UCAO) causes benign oligemia in mice, yet leads to various outcomes (asymptomatic-to-death) in humans. We hypothesized that inhibition of nitric oxide synthase (NOS) both transforms UCAO-mediated oligemia into full infarction and expands pre-existing infarction. Methods: Using 900 mice, we i) investigated stroke-related effects of UCAO with/without intraperitoneal administration of the NOS inhibitor (NOSi) Nω-nitro-L-arginine methyl ester (L-NAME, 400 mg/kg); ii) examined the rescue effect of the NO-donor, molsidomine (200 mg/kg at 30 minutes); and iii) tested the impact of antiplatelet medications. To corroborate preclinical findings, we conducted clinical studies. Results: UCAO alone induced infarction rarely (~2%) or occasionally (~14%) in C57BL/6 and BALB/c mice, respectively. However, L-NAME+UCAO induced large-arterial infarction in ~75% of C57BL/6 and BALB/c mice. Six-hour laser-speckle imaging detected spreading ischemia in ~40% of C57BL/6 and BALB/c mice with infarction (vs. none without) by 24-hours. In agreement with vasoconstriction/microthrombus formation shown by intravital-microscopy, molsidomine and the endothelial-NOS-activating antiplatelet cilostazol attenuated/prevented progression to infarction. Moreover, UCAO without L-NAME caused infarction in ~22% C57BL/6 and ~31% ApoE knock-out mice with hyperglycemia/hyperlipidemia, which associated with ~60% greater levels of symmetric dimethylarginine (SDMA, an endogenous NOSi). Further, increased levels of glucose and cholesterol associated with significantly larger infarct volumes in 438 UCAO-stroke patients. Lastly, Mendelian randomization identified a causative role of NOS inhibition (elevated SDMA concentration) in ischemic stroke risk (OR = 1.24; 95% CI, 1.11–1.38; P = 7.69×10-5). Conclusion: NOS activity determines the fate of hypoperfused brain following acute UCAO, where SDMA could be a potential risk predictor.
ISSN
1838-7640
URI
https://hdl.handle.net/10371/216403
DOI
https://doi.org/10.7150/thno.104132
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  • College of Medicine
  • Department of Medicine
Research Area 뇌경색, 뇌졸중, 혈관성 인지장애 및 치매

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