期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 25, 期 6, 页码 722-729出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600070
关键词
embolic stroke; endothelial nitric oxide synthase; neuroprotection; reperfusion; tissue plasminogen activator
资金
- NHLBI NIH HHS [R01 HL052233-05, R01 HL052233-08, R01 HL070274-01, R01 HL057818, R01 HL070274-03, R01 HL052233-07, R01 HL070274, R01 HL052233, R01 HL052233-06, R01 HL057818-09, R01 HL070274-02] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062729-01A1, R01 DK062729-02, R01 DK062729] Funding Source: Medline
- NINDS NIH HHS [P50-NS10828, P50 NS010828-290036, R01 NS033335, P50 NS010828-320037, R01 NS048426, P50 NS010828-300036, P50 NS010828, R01 NS048426-04, P01 NS010828, R01 NS033335-13, P01 NS010828-330036] Funding Source: Medline
Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wildtype mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.
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