Sun Wen-Tao, Xue Hong-Mei, Hou Hai-Tao, Chen Huan-Xin, Wang Jun, He Guo-Wei, Yang Qin
Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
School of Medicine, Nankai University, Tianjin, China.
Ann Transl Med. 2021 Apr;9(8):625. doi: 10.21037/atm-20-6821.
Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease. We previously demonstrated that disruption of calcium-activated potassium (K) channel activity is involved in homocysteine-induced dilatory dysfunction of porcine coronary arteries. Recently we reported that the K channel family, including large-, intermediate-, and small-conductance K (BK, IK, and SK) subtypes, are abundantly expressed in human internal mammary artery (IMA). In this study, we further investigated whether homocysteine affects the expression and functionality of the K channel family in this commonly used graft for coronary artery bypass surgery (CABG).
Residual IMA segments obtained from patients undergoing CABG were studied in a myograph for the role of K subtypes in both vasorelaxation and vasoconstriction. The expression and distribution of K subtypes were detected by Western blot and immunohistochemistry.
Both the BK channel activator NS1619 and the IK/SK channel activator NS309 evoked significant IMA relaxation. Homocysteine exposure suppressed NS1619-induced relaxation whereas showed no influence on NS309-induced response. Blockade of BK but not IK and SK subtypes significantly suppressed acetylcholine-induced relaxation and enhanced U46619-induced contraction. Homocysteine compromised the vasodilating activity of the BK subtype in IMA, associated with a lowered protein level of the BK β1-subunit. Homocysteine potentiated the role of IK and SK subtypes in mediating endothelium-dependent relaxation without affecting the expression of these channels.
Homocysteine reduces the expression of BK β1-subunit and compromises the vasodilating activity of BK channels in IMA. Unlike BK, IK and SK subtypes are unessential for IMA vasoregulation, whereas the loss of BK functionality in hyperhomocysteinemia enhances the role of IK and SK subtypes in mediating endothelial dilator function. Targeting BK channels may form a strategy to improve the postoperative graft performance in CABG patients with hyperhomocysteinemia who receive IMA grafting.
高同型半胱氨酸血症是动脉粥样硬化性心脏病的独立危险因素。我们之前证明，钙激活钾（K）通道活性的破坏参与了同型半胱氨酸诱导的猪冠状动脉舒张功能障碍。最近我们报道，包括大电导、中电导和小电导K（BK、IK和SK）亚型在内的K通道家族在人乳内动脉（IMA）中大量表达。在本研究中，我们进一步研究了同型半胱氨酸是否影响这种常用于冠状动脉旁路移植术（CABG）的移植物中K通道家族的表达和功能。
从接受CABG的患者获取的残余IMA节段在肌动描记器中进行研究，以探讨K亚型在血管舒张和血管收缩中的作用。通过蛋白质印迹法和免疫组织化学检测K亚型的表达和分布。
BK通道激活剂NS1619和IK/SK通道激活剂NS309均引起IMA显著舒张。同型半胱氨酸暴露抑制了NS1619诱导的舒张，而对NS309诱导的反应无影响。阻断BK亚型而非IK和SK亚型可显著抑制乙酰胆碱诱导的舒张并增强U46619诱导的收缩。同型半胱氨酸损害了IMA中BK亚型的舒张活性，这与BKβ1亚基的蛋白水平降低有关。同型半胱氨酸增强了IK和SK亚型在介导内皮依赖性舒张中的作用，而不影响这些通道的表达。
同型半胱氨酸降低了IMA中BKβ1亚基的表达并损害了BK通道的舒张活性。与BK不同，IK和SK亚型对IMA血管调节并非必需，而高同型半胱氨酸血症中BK功能的丧失增强了IK和SK亚型在介导内皮舒张功能中的作用。针对BK通道可能形成一种策略，以改善接受IMA移植的高同型半胱氨酸血症CABG患者的术后移植物性能。
