Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy.
University Hospital Centre Vaudois (CHUV), Cardiovascular Research Center, Lausanne, Switzerland.
Basic Res Cardiol. 2016 Mar;111(2):12. doi: 10.1007/s00395-016-0533-x. Epub 2016 Jan 19.
The injury caused by myocardial reperfusion after ischemia can be contained by interventions aimed at reducing the inflammation and the oxidative stress that underlie exacerbation of tissue damage. Sphingolipids are a class of structural and signaling lipid molecules; among them, the inflammation mediator ceramide accumulates in the myocardium upon ischemia/reperfusion. Here, we show that, after transient coronary occlusion in mice, an increased de novo ceramide synthesis takes place at reperfusion in the ischemic area surrounding necrosis (area at risk). This correlates with the enhanced expression of the first and rate-limiting enzyme of the de novo pathway, serine palmitoyltransferase (SPT). The intraventricular administration at reperfusion of myriocin, an inhibitor of SPT, significantly protected the area at risk from damage, reducing the infarcted area by 40.9 % relative to controls not treated with the drug. In the area at risk, myriocin downregulated ceramide, reduced the content in other mediators of inflammation and reactive oxygen species, and activated the Nrf2-HO1 cytoprotective response. We conclude that an enhanced ceramide synthesis takes part in ischemia/reperfusion injury and that myriocin treatment can be proposed as a strategy for myocardial pharmacological postconditioning.
缺血后再灌注引起的心肌损伤可以通过干预措施来控制，这些干预措施旨在减轻炎症和氧化应激，从而加剧组织损伤。鞘脂是一类结构和信号脂质分子；其中，炎症介质神经酰胺在缺血/再灌注时在心肌中积累。在这里，我们发现在小鼠短暂性冠状动脉闭塞后，在缺血区（危险区）的再灌注时，新合成的神经酰胺合成增加。这与鞘氨醇磷酸转移酶（SPT），即新途径的第一限速酶的表达增强相关。再灌注时在心室内给予鞘氨醇磷酸转移酶抑制剂——米诺环素，可以显著保护危险区免受损伤，与未用药物治疗的对照组相比，梗死面积减少了 40.9%。在危险区，米诺环素下调了神经酰胺，减少了其他炎症和活性氧物质的介质含量，并激活了 Nrf2-HO1 细胞保护反应。我们得出结论，增强的神经酰胺合成参与了缺血/再灌注损伤，米诺环素治疗可以作为心肌药理学后处理的一种策略。
