Excellence Cluster Cardio-Pulmonary System, University of Giessen Lung Center, Department of Internal Medicine II, Justus-Liebig-University Giessen, Giessen, Germany.
Respir Res. 2011 Feb 4;12(1):20. doi: 10.1186/1465-9921-12-20.
Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.
We investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.
OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV.
These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG.
低氧性肺血管收缩（HPV）是肺部的一种重要机制，它使血液灌注与肺泡通气相匹配，以优化气体交换。最近，我们已经证明，急性但非持续的 HPV 严重依赖于经典瞬时受体电位 6（TRPC6）通道。然而，急性 HPV 期间 TRPC6 的激活机制仍不清楚。我们假设二酰基甘油（DAG）依赖性的 TRPC6 激活调节急性 HPV。
我们研究了二酰基甘油类似物 1-油酰基-2-乙酰基-sn-甘油（OAG）对 TRPC6 缺陷型和野生型小鼠离体灌注和通气肺中的正常氧血管张力的影响。此外，我们还研究了 OAG、二酰基甘油激酶抑制剂 R59949 和磷脂酶 C 抑制剂 U73122 对 HPV 强度的影响，以及它们对血栓素类似物 U46619 引起的非低氧诱导的血管收缩的影响。
OAG 增加了野生型小鼠肺中的正常氧血管张力，但在 TRPC6 缺陷型小鼠的肺中没有增加。在反复低氧通气的情况下，OAG 和 R59949 剂量依赖性地减弱了急性 HPV 的强度，而 U46619 引起的血管收缩没有减少。与 OAG 一样，R59949 模拟了 HPV，因为它在正常氧通气期间引起了剂量依赖性的血管收缩。相比之下，DAG 合成的抑制剂 U73122 抑制了急性 HPV，而其无活性形式 U73343 对 HPV 没有影响。
这些发现支持了这样的结论，即急性 HPV 的 TRPC6 依赖性是通过 DAG 诱导的。
