Regulation of ATP-sensitive K^+ channel gene expression in myocardial ischemia

心肌ATP敏感性钾通道(K&lt；ATP&gt；)被认为是由一个内向整流钾通道(Kir6.1和/或Kir6.2)亚基和磺脲受体(SUR2)组成的复合体。我们检测了这些基因在心肌缺血大鼠中的转录表达。60 mm心肌局部缺血再灌流24-72 h和持续缺血24 h后，Kir6.1mRNA不仅在缺血区(2.7-3.1倍)特异性上调，而且在非缺血区(2.0-2.6-fo1d)也特异性上调。相反，Kir6.2和SUR2的mRNAs在这些缺血过程中保持不变。Western blotting显示，大鼠心脏在60 mm的缺血再灌注24 h后，其缺血区和非缺血区的Kir6.1蛋白水平均有类似的增加。这些发现表明，体液和/或血流动力学因素是导致Kir6.1基因延迟和特异性上调的原因。在接下来的研究中，血管紧张素II 1型受体拮抗剂TCV-116可完全抑制大鼠冠状动脉结扎60 mm再灌流24 h后两个部位Kir6.1mRNA和蛋白的表达上调，而血管紧张素转换酶(ACE)抑制剂赖诺普利可部分抑制这一上调。此外，除经TCV-116处理的大鼠外，在非缺血区和缺血区，Kir6.1的mRNA水平与脑钠素(BNP)的水平呈正相关。脑钠素(BNP)是局部壁应力的分子指标。与假手术组大鼠相比，心肌缺血对照组大鼠血浆Ang II水平无明显升高。因此，应激诱导的组织Ang II的释放调节心肌缺血时心脏Kir6.1mRNA和蛋白表达的特异性诱导。

The cardiac ATP-sensitive potassium (K_<ATP>) channel is thought to be a complex composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the sulfonylurea receptor (SUR2). We examined the transcriptional expression of these genes in rats with myocardial ischemia. Both 60 mm of myocardial regional ischemia followed by 24-72 h of reperfusion and 24 h of continuous ischemia without reperfusion specifically upregulated Kir6.1 mRNA not only in the ischemic (2.7-3.1-fold) but also in the non-ischemic (2.0-2.6-fo1d) region of the left ventricle. In contrast, mRNAs for Kir6.2 and SUR2 remained unchanged under these ischemic procedures. Western blotting demonstrated similar increases in the Kir6.1 protein level both in the ischemic (2.4-fold) and the non-ischemic (2.2-fold) region of rat hearts subjected to 60 mm of ischemia followed by 24 h of reperfusion. These findings suggest that humoral and/or hemodynamic factors are responsible for this delayed and specific up-regulation of Kir6.1. In the next study, pretreatment with TCV-116, an angiotensin (Ang) II type .1 receptor antagonist, completely inhibited the upregulation of Kir6.1 mRNA and protein expression in both regions of rat hearts subjected to 60 mm of coronary artery occlusion followed by 24 h of reperfusion ; whereas pretreatment with lisinopril, an Ang converting enzyme (ACE) inhibitor, partly inhibited this upregulation. In addition, except for rats pretreated with TCV-116, Kir6.1 mRNA levels were positively correlated with those for brain natriuretic peptide (BNP), a molecular indicator of regional wall stress, in both the non-ischemic and the ischemic regions. Plasma Ang II levels were not elevated in rats with control myocardial ischemia compared .with sham rats. Thus, stress-induced release of tissue Ang II regulates the specific induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia.