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小电导钙激活钾通道激活剂可预防小鼠和糖尿病患者的冠状动脉内皮功能障碍。

Coronary endothelial dysfunction prevented by small-conductance calcium-activated potassium channel activator in mice and patients with diabetes.

机构信息

Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence, RI.

Cardiovascular Research Center, Rhode Island Hospital, Providence, RI.

出版信息

J Thorac Cardiovasc Surg. 2020 Dec;160(6):e263-e280. doi: 10.1016/j.jtcvs.2020.01.078. Epub 2020 Feb 19.

DOI:10.1016/j.jtcvs.2020.01.078
PMID:32199659
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7439127/
Abstract

OBJECTIVE

To investigate coronary endothelial protection of a small-conductance calcium-activated potassium (SK) channel activator against a period of cardioplegic-hypoxia and reoxygenation (CP-H/R) injury in mice and patients with diabetes (DM) and those without diabetes (nondiabetic [ND]).

METHODS

Mouse small coronary arteries/heart endothelial cells (MHECs) and human coronary arterial endothelial cells (HCAECs) were dissected from the harvested hearts of mice (n = 16/group) and from discarded right atrial tissue samples of patients with DM and without DM (n = 8/group). The SK current density of MHECs was measured. The in vitro small arteries/arterioles, MHECs, and HCAECs were subjected to 60 minutes of CP hypoxia, followed by 60 minutes of oxygenation. Vessels were treated with or without the selective SK activator NS309 for 5 minutes before and during CP hypoxia.

RESULTS

DM and/or CP-H/R significantly inhibited the total SK currents of MHECs and HCAECs and significantly diminished the mouse coronary relaxation response to NS309. Administration of NS309 immediately before and during CP hypoxia significantly improved the recovery of coronary endothelial function, as demonstrated by increased relaxation responses to adenosine 5'-diphosphate and substance P compared with those seen in controls (P < .05). This protective effect was more pronounced in vessels from ND mice and patients compared with DM mice and patients (P < .05). Cell surface membrane SK3 expression was significantly reduced after hypoxia, whereas cytosolic SK3 expression was greater than that of the sham control group (P < .05).

CONCLUSIONS

Application of NS309 immediately before and during CP hypoxia protects mouse and human coronary microvasculature against CP-H/R injury, but this effect is diminished in the diabetic coronary microvasculature. SK inhibition/inactivation and/or internalization/redistribution may contribute to CP-H/R-induced coronary endothelial and vascular relaxation dysfunction.

摘要

目的

研究小电导钙激活钾（SK）通道激活剂对小鼠、糖尿病（DM）和非糖尿病（ND）患者心脏停搏-缺氧/再复氧（CP-H/R）损伤期间的冠状动脉内皮保护作用。

方法

从小鼠（n=16/组）和 DM 及非 DM 患者（n=8/组）废弃的右心房组织中分离出小鼠小冠状动脉/心脏内皮细胞（MHEC）和人冠状动脉内皮细胞（HCAEC）。测量 MHEC 的 SK 电流密度。将离体小动脉/小动脉、MHEC 和 HCAEC 在 CP 缺氧 60 分钟后，再进行 60 分钟的复氧。在 CP 缺氧前和缺氧期间，用或不用选择性 SK 激活剂 NS309 处理血管 5 分钟。

结果

DM 和/或 CP-H/R 显著抑制了 MHEC 和 HCAEC 的总 SK 电流，并显著降低了 NS309 对小鼠冠状动脉舒张反应。CP 缺氧前和缺氧期间立即给予 NS309 处理，可显著改善冠状动脉内皮功能的恢复，表现为与对照组相比，对腺苷 5'-二磷酸和 P 物质的舒张反应增加（P<.05）。与 DM 小鼠和患者相比，ND 小鼠和患者的血管具有更明显的保护作用（P<.05）。缺氧后细胞表面膜 SK3 表达明显减少，而细胞浆 SK3 表达大于假手术对照组（P<.05）。

结论

CP 缺氧前和缺氧期间应用 NS309 可保护小鼠和人冠状动脉微血管免受 CP-H/R 损伤，但这种作用在糖尿病冠状动脉微血管中减弱。SK 抑制/失活和/或内化/重分布可能导致 CP-H/R 诱导的冠状动脉内皮和血管舒张功能障碍。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/f5598ee02c28/nihms-1564237-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/91ad10700935/nihms-1564237-f0010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/331105105a3c/nihms-1564237-f0012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/7f054f603af1/nihms-1564237-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/c2f40e2c7a37/nihms-1564237-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/0741b1257f3b/nihms-1564237-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/c154ac57730d/nihms-1564237-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/f5598ee02c28/nihms-1564237-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/91ad10700935/nihms-1564237-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/3b9a671bb9c6/nihms-1564237-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/331105105a3c/nihms-1564237-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/b180ac4e15a2/nihms-1564237-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbdf/7439127/7f054f603af1/nihms-1564237-f0002.jpg
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