title: Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells.
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.
authors.affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Chao-Liang
authors.initials: CL
authors.lastname: Long
authors.affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Drug Research Center, Thadweik Academy of Medicine, Beijing 100039, China.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Cui
authors.affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
mesh_terms: D000498:Allyl Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005905:Glyburide / Q000031:analogs & derivatives / Q000494:pharmacology; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy*; D007545:Isoproterenol; D054086:KATP Channels / Q000819:agonists*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D011437:Propylamines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D040901:Proteomics; D051381:Rats; D064233:Sulfonylurea Receptors / Q000819:agonists*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000498:Allyl Compounds; D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D011437:Propylamines; D064233:Sulfonylurea Receptors; C556401:natakalim; C092520:uK-ATP-1 potassium channel; D020097:Natriuretic Peptide, Brain; D007545:Isoproterenol; D005905:Glyburide