Alteration of KCa Channel Function by Homocysteine in Human Internal Mammary Artery

Abstract

ObjectivesHyperhomocysteinemia is an independent risk factor for cardiovascular disease. We previously in porcine coronary arteries demonstrated that disruption of KCa channel activity is involved in homocysteine‐induced impairment of dilatory function. Whether homocysteine affects KCa channels in human arteries remains uninvestigated. In the present study, we aimed to investigate the effect of homocysteine on the expression and functionality of the members of KCa channel family, including large‐ (BKCa), intermediate‐ (IKCa) and small‐ (SKCa) conductance KCa channels in human internal mammary artery (IMA).MethodsResidual IMA segments collected from patients undergoing coronary artery bypass grafting (CABG) were used for myography study for KCa subtype‐mediated relaxation and contraction. Western blot and immunohistochemistry were employed to detect the expression and distribution of KCa subtypes in IMA.ResultsBKCa subtype in the KCa channel family significantly regulated the vasoreactivity of IMA. Blockade of BKCa channels inhibited acetylcholine‐induced relaxation and enhanced U46619‐induced contraction. In comparison, both IKCa and SKCa subtypes played a minor role in the control of relaxation and contraction of IMA. Exposure to homocysteine compromised the vasodilating activity of the BKCa subtype in IMA, evidenced by the suppressed relaxant response to the BKCa channel opener and the decreased impact of the BKCa channel blocker on acetylcholine‐induced relaxation and U46619‐evoked contraction. The functional loss of BKCa was associated with a downregulation of the protein expression of BKCa β1 subunits in the smooth muscle of IMA. Inhibition of endoplasmic reticulum (ER) stress showed protective effect against homocysteine on the function and expression of BKCa channels. In contrast, the role of IKCa and SKCa subtypes in mediating endothelium‐dependent relaxation was augmented by homocysteine though no alterations in the regulatory capacity on vasoconstriction were observed. Homocystine did not alter the protein expression level of IKCa and SKCa subtypes.ConclusionsHomocysteine compromises the vasodilating activity of BKCa channels in IMA, which may be attributed to the loss of BKCa β1 subunits mediated by ER stress. Unlike BKCa, IKCa and SKCa subtypes are unessential for vasoregulation in IMA, the loss of BKCa functionality in hyperhomocysteinemia enhances the role of IKCa and SKCa in mediating endothelial dilator function. Targeting BKCa may form a strategy to improve the postoperative graft performance in CABG patients with hyperhomocysteinemia who receives IMA grafting.Support or Funding InformationSupported by NSFC 81870227 & 81870288, Tianjin Science and Technology Commission (18PTZWHZ00060) & Binhai New Area Health Bureau (2018BWKZ005), and Non‐profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2018TX31002 & 2019XK310001.