远隔缺血预处理在猪和大鼠信号转导中的迷走-脾轴。
Vago-Splenic Axis in Signal Transduction of Remote Ischemic Preconditioning in Pigs and Rats.
机构信息
From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Germany (H.R.L., P.K., A.S., H.H., G.H.).
School of Biomedical Sciences, Kent State University, OH (W.M.C.).
出版信息
Circ Res. 2018 Oct 26;123(10):1152-1163. doi: 10.1161/CIRCRESAHA.118.313859.
RATIONALE
The signal transduction of remote ischemic conditioning is still largely unknown.
OBJECTIVE
Characterization of neurohumoral signal transfer and vago-splenic axis in remote ischemic preconditioning (RIPC).
METHODS AND RESULTS
Anesthetized pigs were subjected to 60 minutes of coronary occlusion and 180 minutes of reperfusion (placebo+ischemia/reperfusion [PLA+I/R]). RIPC was induced by 4×5/5 minutes of hindlimb I/R 90 minutes before coronary occlusion (RIPC+I/R). Arterial blood samples were taken after placebo or RIPC before I/R. In subgroups of pigs, bilateral cervical vagotomy, splenectomy, or splenic denervation were performed before PLA+I/R or RIPC+I/R, respectively. In pigs with RIPC+I/R, infarct size (percentage of area at risk) was less than in those with PLA+I/R (23±12% versus 45±8%); splenectomy or splenic denervation abrogated (splenectomy+RIPC+I/R: 38±15%; splenic denervation+RIPC+I/R: 43±5%), and vagotomy attenuated (vagotomy+RIPC+I/R: 36±11%) RIPC protection. RIPC increased phosphorylation of STAT3 (signal transducer and activator of transcription 3) in left ventricular biopsies taken at early reperfusion. Splenectomy or splenic denervation, but not vagotomy, abolished this increased phosphorylation. In rats with vagotomy, splenectomy, or splenic denervation, RIPC (3×5/5 minutes of hindlimb occlusion/reperfusion) or placebo was performed, respectively. Hearts were isolated, saline perfused, and subjected to 30/120-minute global I/R. With RIPC, infarct size (percentage of ventricular mass) was less (20±7%) than with placebo (37±6%), and vagotomy, splenectomy, or splenic denervation abrogated RIPC protection (38±12%, 36±9%, and 36±7%), respectively. Rat spleens were isolated, saline perfused, and splenic effluate (SEff) was sampled after infusion with carbachol (SEff) or saline (SEff). Pig plasma or SEff was infused into isolated perfused rat hearts subjected to global I/R. Infarct size was less with infusion of RIPC+I/R+ (24±6%) than with PLA+I/R (40±8%), vagotomy+PLA+I/R (39±11%), splenectomy+PLA+I/R (35±8%), vagotomy+RIPC+I/R (40±9%), splenectomy+RIPC+I/R (33±9%), or splenic denervation+RIPC+I/R (39±8%), respectively. With infusion of SEff, infarct size was less than with infusion of SEff (24 [19-27]% versus 35 [32-38]%).
CONCLUSIONS
Activation of a vago-splenic axis is causally involved in RIPC cardioprotection.
原理
远程缺血预处理的信号转导仍在很大程度上未知。
目的
描述神经激素信号转导和迷走-脾轴在远程缺血预处理（RIPC）中的作用。
方法和结果
在麻醉的猪中进行 60 分钟的冠状动脉闭塞和 180 分钟的再灌注（安慰剂+缺血/再灌注 [PLA+I/R]）。在冠状动脉闭塞前 90 分钟，通过 4×5/5 分钟的后肢 I/R 诱导 RIPC（RIPC+I/R）。在 PLA+I/R 或 RIPC+I/R 之前，在安慰剂或 RIPC 后从动脉血样中取样。在猪的亚组中，在 PLA+I/R 或 RIPC+I/R 之前分别进行双侧颈迷走神经切断术、脾切除术或脾神经切除术。在接受 RIPC+I/R 的猪中，梗死面积（危险区域面积的百分比）小于接受 PLA+I/R 的猪（23±12%比 45±8%）；脾切除术或脾神经切除术（脾切除术+RIPC+I/R：38±15%；脾神经切除术+RIPC+I/R：43±5%）和迷走神经切断术减弱（迷走神经切断术+RIPC+I/R：36±11%）RIPC 保护作用。RIPC 增加了左心室活检在早期再灌注时磷酸化 STAT3（信号转导和转录激活因子 3）。脾切除术或脾神经切除术，但不是迷走神经切断术，消除了这种磷酸化的增加。在接受迷走神经切断术、脾切除术或脾神经切除术的大鼠中，分别进行 RIPC（3×5/5 分钟的后肢闭塞/再灌注）或安慰剂。心脏被分离出来，用盐水灌注，并进行 30/120 分钟的整体 I/R。与安慰剂相比，RIPC（20±7%）减少了梗死面积（心室质量的百分比）（37±6%），迷走神经切断术、脾切除术或脾神经切除术消除了 RIPC 的保护作用（38±12%、36±9%和 36±7%）。从盐水灌注的大鼠脾脏中分离出脾脏流出物（SEff）并取样，然后用卡巴胆碱（SEff）或生理盐水（SEff）输注。将猪血浆或 SEff 输注到接受整体 I/R 的分离灌注的大鼠心脏中。与 PLA+I/R（40±8%）、迷走神经切断术+PLA+I/R（39±11%）、脾切除术+PLA+I/R（35±8%）、迷走神经切断术+RIPC+I/R（40±9%）、脾切除术+RIPC+I/R（33±9%）或脾神经切除术+RIPC+I/R（39±8%）相比，输注 RIPC+I/R+（24±6%）时梗死面积较小。与 SEff 输注相比，输注 SEff 时梗死面积较小（24[19-27]%比 35[32-38]%）。
结论
迷走-脾轴的激活是 RIPC 心脏保护作用的一个因果关系。
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