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 (K ATP ) 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 K ATP 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.

Nicorandil Attenuates LPS-Induced Acute Lung Injury by Pulmonary Endothelial Cell Protection via NF-κB and MAPK Pathways

“…In mice, knockout of endothelial specific Kir6.1 leads to impaired vasorelaxation during hypoxia in the coronary circulation [ 44 ]. In HPAECs, KCOs are capable of reducing endothelial apoptosis, promoting the release of nitrogen oxide and preventing EC dysfunction from ischemia and hypoxia, which could be blocked by K ATP channel blockers [ 9 , 45 , 46 ]. Although the present study showed that K ATP channels played important roles in regulating EC functions, the mouse model with knockout of endothelial specific K ATP channels may be used for further studies to demonstrate the protective effects of K ATP channels on ECs in ALI.…”

KATP channels are regulators of programmed cell death and targets for the creation of novel drugs against ischemia/reperfusion cardiac injury

“…Vascular smooth muscles expressed Kir6.2/SUR2B [34]. The Kir6.1/SUR2B channel is expressed by endothelial cells [35,36]. Neurons express the Kir6.2/SUR1 channel [21,23,24,37,38].…”

“…Iptakalim attenuated cardiac hypertrophy induced by isoproterenol in rats [191]. Nicorandil and natakalim exhibited the same effect in rats receiving isoproterenol [36,192]. Chronic administration of natakalim attenuated cardiac hypertrophy and cardiac failure in rats with permanent CAO [114].…”

Targeting Epigenetic Mechanisms in Vascular Aging

“…For example, testosterone ameliorates vascular aging via the GAS6/AXL signaling pathway ( 79 ). GAS6 signaling is reported to increase NO bioavailability via the androgen receptor-mediated activation of endothelial NO synthase (eNOS) ( 80 ). Testosterone may also function via lncRNA-SWI/SNF complex crosstalk ( 81 ).…”