TMEM16A 参与冠状动脉血流的调节，并且在高血压中发生改变。
TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension.
机构信息
Vascular Biology Research Centre, Institute of Molecular and Clinical Sciences, St George's University of London, London, UK.
Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
出版信息
Br J Pharmacol. 2019 Jun;176(11):1635-1648. doi: 10.1111/bph.14598. Epub 2019 Apr 11.
BACKGROUND AND PURPOSE
Coronary artery disease leads to ischaemic heart disease and ultimately myocardial infarction. Thus, it is important to determine the factors that regulate coronary blood flow. Ca -activated chloride channels contribute to the regulation of arterial tone; however, their role in coronary arteries is unknown. The aim of this study was to investigate the expression and function of the main molecular correlate of Ca -activated chloride channels, TMEM16A, in rat coronary arteries.
EXPERIMENTAL APPROACH
We performed mRNA and protein analysis, electrophysiological studies of coronary artery myocytes, and functional studies of coronary artery contractility and coronary perfusion, using novel inhibitors of TMEM16A. Furthermore, we assessed whether any changes in expression and function occurred in coronary arteries from spontaneously hypertensive rats (SHRs).
KEY RESULTS
TMEM16A was expressed in rat coronary arteries. The TMEM16A-specific inhibitor, MONNA, hyperpolarised the membrane potential in U46619. MONNA, T16A -A01, and Ani9 attenuated 5-HT/U46619-induced contractions. MONNA and T16A -A01 also increased coronary flow in Langendorff perfused rat heart preparations. TMEM16A mRNA was increased in coronary artery smooth muscle cells from SHRs, and U46619 and 5-HT were more potent in arteries from SHRs than in those from normal Wistar rats. MONNA diminished this increased sensitivity to U46619 and 5-HT.
CONCLUSIONS AND IMPLICATIONS
In conclusion, TMEM16A is a key regulator of coronary blood flow and is implicated in the altered contractility of coronary arteries from SHRs.
背景与目的
冠状动脉疾病导致缺血性心脏病，最终导致心肌梗死。因此，确定调节冠状动脉血流的因素非常重要。钙激活氯离子通道有助于调节动脉张力；然而，它们在冠状动脉中的作用尚不清楚。本研究旨在研究调节动脉张力的主要分子相关物钙激活氯离子通道的主要分子相关物 TMEM16A 在大鼠冠状动脉中的表达和功能。
实验方法
我们进行了 mRNA 和蛋白质分析、冠状动脉心肌细胞的电生理研究以及冠状动脉收缩性和冠状动脉灌注的功能研究，使用 TMEM16A 的新型抑制剂。此外，我们评估了自发性高血压大鼠（SHR）的冠状动脉中是否发生了任何表达和功能变化。
主要结果
TMEM16A 在大鼠冠状动脉中表达。TMEM16A 特异性抑制剂 MONNA 使 U46619 去极化。MONNA、T16A-A01 和 Ani9 减弱了 5-HT/U46619 诱导的收缩。MONNA 和 T16A-A01 还增加了 Langendorff 灌注大鼠心脏标本中的冠状动脉流量。冠状动脉平滑肌细胞中的 TMEM16A mRNA 在 SHR 的冠状动脉中增加，U46619 和 5-HT 在 SHR 的动脉中比在正常 Wistar 大鼠的动脉中更有效。MONNA 减弱了这种对 U46619 和 5-HT 的敏感性增加。
结论和意义
总之，TMEM16A 是冠状动脉血流的关键调节剂，与 SHR 冠状动脉收缩性改变有关。
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