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

Autor: Kim H; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Chung J; Medical Science Research Center, Dongguk University, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Kang JW; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Schellingerhout D; Departments of Neuroradiology and Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA., Lee SJ; Genome & Health Big Data Laboratory, Department of Public Health, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea.; Health & Environment Institute, Seoul National University, Seoul 08826, Republic of Korea.; Genomic Medicine Institute, Seoul National University, Seoul 08826, Republic of Korea., Jang HJ; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Park I; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Kim T; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Gwak DS; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Lee JS; Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea., Hong SH; Center for Translational Neuromedicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA., Je KH; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea., Bae HJ; Department of Neurology and Cerebrovascular Center, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea., Sung J; Genome & Health Big Data Laboratory, Department of Public Health, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea.; Health & Environment Institute, Seoul National University, Seoul 08826, Republic of Korea.; Genomic Medicine Institute, Seoul National University, Seoul 08826, Republic of Korea., Lo EH; Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA., Faber J; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.; Curriculum in Neuroscience, University of North Carolina, Chapel Hill, NC 27599, USA.; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA., Ayata C; Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.; Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02114, USA., Kim DE; Department of neurology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea.; Medical Science Research Center, Dongguk University, Goyang 10326, Republic of Korea.; National Priority Research Center for Stroke, Goyang 10326, Republic of Korea.
Jazyk: angličtina
Zdroj: Theranostics [Theranostics] 2025 Jan 01; Vol. 15 (2), pp. 585-604. Date of Electronic Publication: 2025 Jan 01 (Print Publication: 2025).
DOI: 10.7150/thno.104132
Abstrakt: 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) N ω -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.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)
Databáze: MEDLINE
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