UvA-DARE ( Digital Academic Repository ) Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats
UvA-DARE ( Digital Academic Repository ) Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats
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发表时间：
2012
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通讯作者：
L. Spijkers;B. Janssen;J. Nelissen;Merlijn J Meens;D. Wijesinghe;C. Chalfant;J. Mey;A. Alewijnse;S. Peters
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作者：
L. Spijkers;B. Janssen;J. Nelissen;Merlijn J Meens;D. Wijesinghe;C. Chalfant;J. Mey;A. Alewijnse;S. Peters
背景资料：我们以前已经表明，人类和自发性高血压大鼠（SHR）的原发性高血压与神经酰胺水平的增加和鞘脂生物学的显著改变有关。SHR离体颈动脉中神经酰胺的药理学升高通过钙非依赖性磷脂酶A2、环氧合酶-1和血栓素A2的血栓素酶依赖性释放导致血管收缩。这种现象在血压正常的Wistar京都（WKY）大鼠的血管中几乎不存在。在这里，我们研究了降低血压是否可以逆转升高的神经酰胺水平，并减少神经酰胺介导的收缩SHR。方法和结果：为此，SHR用血管紧张素II 1型受体拮抗剂氯沙坦或血管扩张剂肼苯哒嗪治疗4周。两种药物均降低血压（未治疗SHR的SBP：19167 mmHg，氯沙坦：12565 mmHg和肼苯哒嗪：113614 mmHg）。血压降低与两组中血管神经酰胺水平降低20-25%和离体颈动脉内皮功能改善相关。有趣的是，氯沙坦，而不是肼苯哒嗪治疗，显着减少鞘磷脂酶诱导的收缩。虽然两种药物都降低了环氧合酶-1的表达，但只有氯沙坦而不是肼苯哒嗪降低了钙非依赖性磷脂酶A2的内皮表达。后一个发现可以解释氯沙坦治疗对鞘磷脂酶诱导的血管收缩的影响。结论：总之，这项研究证实了鞘脂生物学在血压控制中的重要性，并特别表明，降低血压可降低SHR的血管神经酰胺水平，而氯沙坦治疗（而不是降低血压本身）可降低神经酰胺介导的动脉收缩。引文：Spijkers LJA，Janssen BJA，Nelissen J，Meens MJPMT，Wijesinghe D，et al.（2011）Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneous Hypertensive Rats. PLoS ONE 6（12）：e29222. doi：10.1371/journal.pone.0029222编辑器：Joseph Najbauer，City of Hope National Medical Center and Beckman Research Institute，United States of America接收日期2011年8月5日;接受日期2011年11月22日;发布日期2011年12月15日这是一篇开放获取的文章，不受任何版权限制，可以自由复制、分发、传输、修改、构建或以其他方式由任何人用于任何合法目的。该作品在Creative Commons CC 0公有领域贡献下提供。资助：本研究在Top Institute Pharma项目T2-108的框架内进行。CEC和DSW感谢退伍军人管理局（CEC的VA Merit Review I，CEC的研究职业科学家奖和DSW的CDA 1），美国国立卫生研究院（HL 072925）（CEC），CA 117950（CEC）的赠款。资助者在研究设计、数据收集和分析、出版决定或手稿编写中没有任何作用。利益冲突：作者声明不存在利益冲突。* 电子邮件：s.l. amc.uva.nl
Background: We have previously shown that essential hypertension in humans and spontaneously hypertensive rats (SHR), is associated with increased levels of ceramide and marked alterations in sphingolipid biology. Pharmacological elevation of ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A2, cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A2. This phenomenon is almost absent in vessels from normotensive Wistar Kyoto (WKY) rats. Here we investigated whether lowering of blood pressure can reverse elevated ceramide levels and reduce ceramide-mediated contractions in SHR. Methods and Findings: For this purpose SHR were treated for 4 weeks with the angiotensin II type 1 receptor antagonist losartan or the vasodilator hydralazine. Both drugs decreased blood pressure equally (SBP untreated SHR: 19167 mmHg, losartan: 12565 mmHg and hydralazine: 113614 mmHg). The blood pressure lowering was associated with a 20–25% reduction in vascular ceramide levels and improved endothelial function of isolated carotid arteries in both groups. Interestingly, losartan, but not hydralazine treatment, markedly reduced sphingomyelinase-induced contractions. While both drugs lowered cyclooxygenase-1 expression, only losartan and not hydralazine, reduced the endothelial expression of calcium-independent phospholipase A2. The latter finding may explain the effect of losartan treatment on sphingomyelinase-induced vascular contraction. Conclusion: In summary, this study corroborates the importance of sphingolipid biology in blood pressure control and specifically shows that blood pressure lowering reduces vascular ceramide levels in SHR and that losartan treatment, but not blood pressure lowering per se, reduces ceramide-mediated arterial contractions. Citation: Spijkers LJA, Janssen BJA, Nelissen J, Meens MJPMT, Wijesinghe D, et al. (2011) Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats. PLoS ONE 6(12): e29222. doi:10.1371/journal.pone.0029222 Editor: Joseph Najbauer, City of Hope National Medical Center and Beckman Research Institute, United States of America Received August 5, 2011; Accepted November 22, 2011; Published December 15, 2011 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This study was performed within the framework of Top Institute Pharma project T2-108. CEC and DSW acknowledge support by grants from the Veteran’s Administration (VA Merit Review I to CEC, a Research Career Scientist Award to CEC and a CDA1 to DSW), from the National Institutes of Health (HL072925) (CEC), CA117950 (CEC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: s.l.peters@amc.uva.nl