Abstract
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−1·d−1) or Ipt (3 mg·kg−1·d−1) 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−1·d−1), 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.
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Acknowledgements
This work was supported by grants from the National Basic Research “973” Program (Grants No 2012CB518200 and JCKY2013000B001) and the State Key Research Project of China (Grant No AWS11J003).
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Supplementary information is available on Acta Pharmacologica Sinica's web site.
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Supplementary Figure S1
Gene Ontology (GO) functional annotations of all proteins. (DOC 103 kb)
Supplementary Figure S2
Cluster of Orthologous Groups (COG) of all proteins. (DOC 82 kb)
Supplementary Table S1
The differential proteins in the plasma of model and Nat 3mg/kg treated group from three independent biological replicate experiments (DOC 90 kb)
Supplementary Table S2
The differential proteins in the plasma of control and model group from three independent biological replicate experiments (DOC 143 kb)
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Wang, S., Long, Cl., Chen, J. et al. Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells. Acta Pharmacol Sin 38, 41–55 (2017). https://doi.org/10.1038/aps.2016.118
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DOI: https://doi.org/10.1038/aps.2016.118
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