Wang Shang, Long Chao-Liang, Chen Jun, Cui Wen-Yu, Zhang Yan-Fang, Zhang Hao, Wang Hai
Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
Cardiovascular Drug Research Center, Thadweik Academy of Medicine, Beijing 100039, China.
Acta Pharmacol Sin. 2017 Jan;38(1):41-55. doi: 10.1038/aps.2016.118. Epub 2016 Nov 28.
Both iptakalim (Ipt) and natakalim (Nat) activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel (KATP) subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure (ISO-CHF) in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat (1, 3, 9 mg·kg·d) or Ipt (3 mg·kg·d) for 60 days significantly improved cardiac dysfunction, reversed cardiac remodeling, significantly attenuated the pathological increases in BNP levels, and improved endothelial dysfunction by adjusting the balance between endothelin and NO systems. The therapeutic effects of Nat were prevented by the selective KATP blocker glibenclamine (Gli, 50 mg·kg·d), confirming that these effects were mediated through activation of the SUR2B/Kir6.1 channel in endothelial cells. The molecular mechanisms underlying the therapeutic effects of Nat were further addressed using proteomic methods. We identified 724 proteins in the plasma of ISO-CHF rats; 55 proteins were related to Nat. These differentially expressed proteins were mainly involved in single-organism processes and the regulation of biological quality relative to CHF, including proteasome (Psm) and ATP protein clusters. We screened out PRKAR2β, GAS6/eNOS/NO and NO/PKG/VASP pathways involved in the amelioration of CHF among the 24 enriched pathways. We further confirmed 6 protein candidates, including PRKAR2β, GAS6 and VASP, which were involved in the endothelial mechanisms, and ATP, TIMP3 and AGT, which contributed to its cardiovascular actions. This study demonstrates a new pharmacological approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells, and that the eNOS/VASP pathways are involved in its signaling mechanisms.
衣普卡林（Ipt）和纳他卡林（Nat）均可高选择性地激活SUR2B/Kir6.1通道，这是一种ATP敏感性钾通道（KATP）亚型。在本研究中，我们探究了Ipt和Nat对异丙肾上腺素诱导的大鼠慢性心力衰竭（ISO-CHF）的治疗作用，并证明了通过激活内皮细胞中的SUR2B/Kir6.1通道来治疗CHF的一种新方法。在ISO-CHF大鼠中，口服给予Nat（1、3、9mg·kg·d）或Ipt（3mg·kg·d）60天可显著改善心脏功能障碍，逆转心脏重塑，显著减轻BNP水平的病理性升高，并通过调节内皮素和NO系统之间的平衡改善内皮功能障碍。选择性KATP阻滞剂格列本脲（Gli，50mg·kg·d）可阻断Nat的治疗作用，证实这些作用是通过激活内皮细胞中的SUR2B/Kir6.1通道介导的。使用蛋白质组学方法进一步探讨了Nat治疗作用的分子机制。我们在ISO-CHF大鼠血浆中鉴定出724种蛋白质；其中55种蛋白质与Nat有关。这些差异表达的蛋白质主要参与单细胞过程以及与CHF相关的生物学质量调节，包括蛋白酶体（Psm）和ATP蛋白簇。我们在24条富集途径中筛选出参与改善CHF的PRKAR2β、GAS6/eNOS/NO和NO/PKG/VASP途径。我们进一步确认了6种蛋白质候选物，包括参与内皮机制的PRKAR2β以及GAS6和VASP，还有对其心血管作用有贡献的ATP、TIMP3和AGT。本研究证明了通过激活内皮细胞中的SUR2B/Kir6.1通道来治疗CHF的一种新药理学方法，且eNOS/VASP途径参与其信号传导机制。
