Objective C1q/TNF-related protein(CTRP)1 was initiallyidentified as a paralog of adiponectin based on the similarity in C1q domain of these two proteins.Previously,we showed that CTRP1promotes the development of ather...Objective C1q/TNF-related protein(CTRP)1 was initiallyidentified as a paralog of adiponectin based on the similarity in C1q domain of these two proteins.Previously,we showed that CTRP1promotes the development of atherosclerosis by increasing endothelial adhesiveness.Here,we sought to investigate whether CTRP1 also influences vascular dilatory functions.展开更多
Aim Evidence has shown that stimulation of alA-adrenorecetors receptor （alA-AR） or angiotensin II type 1 receptor （AT1R） acutely down-regulates the rapid component of the delayed rectifier K ＋ current （IKr） via...Aim Evidence has shown that stimulation of alA-adrenorecetors receptor （alA-AR） or angiotensin II type 1 receptor （AT1R） acutely down-regulates the rapid component of the delayed rectifier K ＋ current （IKr） via protein kinase C （PKC）. This study was designed to investigate which PKC isozymes mediate down-regulations of IKr by alA-AR and AT1R. Method The whole-cell patch-clamp technique was used to record IKr in native cardio- myocytes and in human embryonic kidney （HEK） 293 cells co-transfected with human ether-a-go-go related gene （hERG） encoding α-subunit of IKr and human alA-AR or AT1R gene. Result In isolated guinea-pig ventricular cardiomyocytes the inhibitory action of Ang II on IKr was little affected by Go6976 （selectively inhibiting PKCα, β and γ） and Go6983 （selectively inhibiting PKCα, β, γ , δ, and ζ）, but was significantly antagonized by an inter- nal dialysis with PKCe-selective inhibitory peptide εV1 -2. In contrast, the inhibitory action of alA-AR agonist A61603 on IKr was remarkably attenuated by Go6976 or Go6983, but not affected by peptide εV1 -2. Moreover, specific PKC-selective inhibitory peptide antagonized the effect of A61603. The results suggested that PKCe and PKCα isoform respectively mediated the inhibitory effect of AT1R and a1A-AR. In heterologous expression system, both PKCα and e-selective activator peptides down regulated hERG current with different manner. PKCα activator peptide shifted the activation curve of the channel to the right, but PKCe-selective activator peptide did not. Simi- larly, A61603 shifted the activation curve to the right, whereas Ang Ⅱ had no effect. In addition, both A61603 and PKCα activator peptide showed inhibitory action on bERG A PKC current （an bERG mutant in which 17 of the 18 ROSITE-predicted PKC acceptor serines/threonines were changed to alanine） with a similar potency to wild type bERG current. But, both Ang Ⅱ and PKCe-selective activator peptide exhibited no effects on bERG △ PKC cur- rent. The results indicated that PKCα and PKCe isoforms down-regulated bERG current through different mecha- nism. Conclusion PKCα and PKCe isoform respectively mediates the inhibition on IKr by stimulation of AT1R and alA-AR via different molecular mechanism.展开更多
文摘Objective C1q/TNF-related protein(CTRP)1 was initiallyidentified as a paralog of adiponectin based on the similarity in C1q domain of these two proteins.Previously,we showed that CTRP1promotes the development of atherosclerosis by increasing endothelial adhesiveness.Here,we sought to investigate whether CTRP1 also influences vascular dilatory functions.
文摘Aim Evidence has shown that stimulation of alA-adrenorecetors receptor （alA-AR） or angiotensin II type 1 receptor （AT1R） acutely down-regulates the rapid component of the delayed rectifier K ＋ current （IKr） via protein kinase C （PKC）. This study was designed to investigate which PKC isozymes mediate down-regulations of IKr by alA-AR and AT1R. Method The whole-cell patch-clamp technique was used to record IKr in native cardio- myocytes and in human embryonic kidney （HEK） 293 cells co-transfected with human ether-a-go-go related gene （hERG） encoding α-subunit of IKr and human alA-AR or AT1R gene. Result In isolated guinea-pig ventricular cardiomyocytes the inhibitory action of Ang II on IKr was little affected by Go6976 （selectively inhibiting PKCα, β and γ） and Go6983 （selectively inhibiting PKCα, β, γ , δ, and ζ）, but was significantly antagonized by an inter- nal dialysis with PKCe-selective inhibitory peptide εV1 -2. In contrast, the inhibitory action of alA-AR agonist A61603 on IKr was remarkably attenuated by Go6976 or Go6983, but not affected by peptide εV1 -2. Moreover, specific PKC-selective inhibitory peptide antagonized the effect of A61603. The results suggested that PKCe and PKCα isoform respectively mediated the inhibitory effect of AT1R and a1A-AR. In heterologous expression system, both PKCα and e-selective activator peptides down regulated hERG current with different manner. PKCα activator peptide shifted the activation curve of the channel to the right, but PKCe-selective activator peptide did not. Simi- larly, A61603 shifted the activation curve to the right, whereas Ang Ⅱ had no effect. In addition, both A61603 and PKCα activator peptide showed inhibitory action on bERG A PKC current （an bERG mutant in which 17 of the 18 ROSITE-predicted PKC acceptor serines/threonines were changed to alanine） with a similar potency to wild type bERG current. But, both Ang Ⅱ and PKCe-selective activator peptide exhibited no effects on bERG △ PKC cur- rent. The results indicated that PKCα and PKCe isoforms down-regulated bERG current through different mecha- nism. Conclusion PKCα and PKCe isoform respectively mediates the inhibition on IKr by stimulation of AT1R and alA-AR via different molecular mechanism.
