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Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells.
Acta Pharmacol Sin. 2017 Jan; 38(1):41-55.AP

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.

Links

Authors+Show Affiliations

Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.

Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.

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.

Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.

Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.

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.

MeSH

Allyl CompoundsAnimalsDose-Response Relationship, DrugEndothelial CellsGlyburideHeart FailureIsoproterenolKATP ChannelsNatriuretic Peptide, BrainPropylaminesProteomicsRatsSulfonylurea ReceptorsVentricular Remodeling

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27890915

Citation

Wang, Shang, et al. "Pharmacological Evidence: a New Therapeutic Approach to the Treatment of Chronic Heart Failure Through SUR2B/Kir6.1 Channel in Endothelial Cells." Acta Pharmacologica Sinica, vol. 38, no. 1, 2017, pp. 41-55.

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. 2017;38(1):41-55.

Wang, S., Long, C. L., Chen, J., Cui, W. Y., Zhang, Y. F., Zhang, H., & Wang, H. (2017). Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells. Acta Pharmacologica Sinica, 38(1), 41-55. https://doi.org/10.1038/aps.2016.118

Wang S, 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. 2017;38(1):41-55. PubMed PMID: 27890915.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells. AU - Wang,Shang, AU - Long,Chao-Liang, AU - Chen,Jun, AU - Cui,Wen-Yu, AU - Zhang,Yan-Fang, AU - Zhang,Hao, AU - Wang,Hai, Y1 - 2016/11/28/ PY - 2016/05/11/received PY - 2016/09/13/accepted PY - 2016/11/29/pubmed PY - 2017/8/5/medline PY - 2016/11/29/entrez SP - 41 EP - 55 JF - Acta pharmacologica Sinica JO - Acta Pharmacol Sin VL - 38 IS - 1 N2 - 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. SN - 1745-7254 UR - https://www.unboundmedicine.com/medline/citation/27890915/Pharmacological_evidence:_a_new_therapeutic_approach_to_the_treatment_of_chronic_heart_failure_through_SUR2B/Kir6_1_channel_in_endothelial_cells_ DB - PRIME DP - Unbound Medicine ER -