Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway.
3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a novel type of soluble guanylyl cyclase (sGC) activator, is useful in investigating the signaling of cGMP and may provide a new approach for treating cardiovascular diseases. Herein, YC-1 was demonstrated to inhibit the generation of superoxide anion (O2-) and the release of beta-glucuronidase release, to diminish the membrane-associated p47phox and to accelerate resequestration of cytosolic calcium in formyl-l-methionyl-l-leucyl-l-phenylalanine-activated human neutrophils. YC-1 not only directly promoted sGC activity and cGMP formation but also dramatically potentiated sodium nitroprusside-induced sGC activity and cGMP formation in human neutrophils. However, the synergistic increase in the amount of cGMP was inconsistent with its cellular response. Moreover, neither an sGC inhibitor nor protein kinase G inhibitors reversed the inhibitory effect of YC-1. Interestingly, YC-1 also increased the cAMP concentration and protein kinase (PK)A activity. The inhibitory effect of YC-1 was significantly enhanced by prostaglandin (PG)E1 and isoproterenol, and almost abolished by PKA inhibitors. These results show that cAMP, but not cGMP, mediates the YC-1-induced inhibition of human neutrophils. YC-1 increased the PGE1- and forskolin-induced but not 3-isobutyl-1-methylxanthine-produced cAMP formation, suggesting inhibition of phosphodiesterase. These findings thus reveal novel mechanism-mediated anti-inflammatory properties of YC-1 in human neutrophils, which can influence the progression of cardiovascular disease. cAMP, but not cGMP, plays an important role in the regulation of respiratory burst and degranulation in human neutrophils.
Hwang
Tsong-Long
TL
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Rd., Kweishan 333, Taoyuan, Taiwan. htl@mail.cgu.edu.tw
Hung
Hsiu-Wen
HW
Kao
Shu-Hui
SH
Teng
Che-Ming
CM
Wu
Chin-Chung
CC
Cheng
Samantha Ju-San
SJ
D000293:Adolescent; D000328:Adult; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism
D020536:Enzyme Activators; D007191:Indazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013481:Superoxides; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP