BACKGROUND AND PURPOSE: The activation of M3 cholinoceptors (M3 receptors) by choline reduces cardiovascular risk, but it is unclear whether these receptors can regulate ischaemia/reperfusion (I/R)-induced vascular injury. Thus, the primary goal of the present study was to explore the effects of choline on the function of mesenteric arteries following I/R, with a major focus on Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulation. EXPERIMENTAL APPROACH: Rats were given choline (10 mg · kg(-1), i.v.) and then the superior mesenteric artery was occluded for 60 min (ischaemia), followed by 90 min of reperfusion. The M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), was injected (0.12 μg · kg(-1), i.v.) 5 min prior to choline treatment. Vascular function was examined in rings of mesenteric arteries isolated after the reperfusion procedure. Vascular superoxide anion production, CaMKII and the levels of Ca(2+)-cycling proteins were also assessed. KEY RESULTS: Choline treatment attenuated I/R-induced vascular dysfunction, blocked elevations in the levels of reactive oxygen species (ROS) and decreased the up-regulated expression of oxidised CaMKII and phosphorylated CaMKII. In addition, choline reversed the abnormal expression of Ca(2+)-cycling proteins, including Na(+)Ca(2+) exchanger, inositol 1,4,5-trisphosphate receptor, sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban. All of these cholinergic effects of choline were abolished by 4-DAMP. CONCLUSIONS AND IMPLICATIONS: Our data suggest that inhibition of the ROS-mediated CaMKII pathway and modulation of Ca(2+)-cycling proteins may be novel mechanisms underlying choline-induced vascular protection. These results represent a significant addition to the understanding of the pharmacological roles of M3 receptors in the vasculature, providing a new therapeutic strategy for I/R-induced vascular injury.
BACKGROUND AND PURPOSE: The activation of M3 cholinoceptors (M3 receptors) by choline reduces cardiovascular risk, but it is unclear whether these receptors can regulate ischaemia/reperfusion (I/R)-induced vascular injury. Thus, the primary goal of the present study was to explore the effects of choline on the function of mesenteric arteries following I/R, with a major focus on Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulation. EXPERIMENTAL APPROACH: Rats were given choline (10 mg · kg(-1), i.v.) and then the superior mesenteric artery was occluded for 60 min (ischaemia), followed by 90 min of reperfusion. The M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), was injected (0.12 μg · kg(-1), i.v.) 5 min prior to choline treatment. Vascular function was examined in rings of mesenteric arteries isolated after the reperfusion procedure. Vascular superoxide anion production, CaMKII and the levels of Ca(2+)-cycling proteins were also assessed. KEY RESULTS:Choline treatment attenuated I/R-induced vascular dysfunction, blocked elevations in the levels of reactive oxygen species (ROS) and decreased the up-regulated expression of oxidised CaMKII and phosphorylated CaMKII. In addition, choline reversed the abnormal expression of Ca(2+)-cycling proteins, including Na(+)Ca(2+) exchanger, inositol 1,4,5-trisphosphate receptor, sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban. All of these cholinergic effects of choline were abolished by 4-DAMP. CONCLUSIONS AND IMPLICATIONS: Our data suggest that inhibition of the ROS-mediated CaMKII pathway and modulation of Ca(2+)-cycling proteins may be novel mechanisms underlying choline-induced vascular protection. These results represent a significant addition to the understanding of the pharmacological roles of M3 receptors in the vasculature, providing a new therapeutic strategy for I/R-induced vascular injury.
Authors: Lahouaria Hadri; Razmig G Kratlian; Ludovic Benard; Bradley A Maron; Peter Dorfmüller; Dennis Ladage; Christophe Guignabert; Kiyotake Ishikawa; Jaume Aguero; Borja Ibanez; Irene C Turnbull; Erik Kohlbrenner; Lifan Liang; Krisztina Zsebo; Marc Humbert; Jean-Sébastien Hulot; Yoshiaki Kawase; Roger J Hajjar; Jane A Leopold Journal: Circulation Date: 2013-06-26 Impact factor: 29.690
Authors: Rajesh Kumar Gandhirajan; Shu Meng; Harish C Chandramoorthy; Karthik Mallilankaraman; Salvatore Mancarella; Hui Gao; Roshanak Razmpour; Xiao-Feng Yang; Steven R Houser; Ju Chen; Walter J Koch; Hong Wang; Jonathan Soboloff; Donald L Gill; Muniswamy Madesh Journal: J Clin Invest Date: 2013-01-25 Impact factor: 14.808
Authors: Stephen P H Alexander; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; Michael Spedding; John A Peters; Anthony J Harmar Journal: Br J Pharmacol Date: 2013-12 Impact factor: 8.739
Authors: Stephen P H Alexander; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; William A Catterall; Michael Spedding; John A Peters; Anthony J Harmar Journal: Br J Pharmacol Date: 2013-12 Impact factor: 8.739
Authors: Hsiang-Ting Ho; Andriy E Belevych; Bin Liu; Ingrid M Bonilla; Przemysław B Radwański; Igor V Kubasov; Héctor H Valdivia; Karsten Schober; Cynthia A Carnes; Sándor Györke Journal: Hypertension Date: 2016-09-19 Impact factor: 10.190