L-arginine chlorination results in the formation of a nonselective nitric-oxide synthase inhibitor.
Reduced nitric oxide (NO) bioavailability and impaired vascular function are the key pathological characteristics of inflammatory diseases such as atherosclerosis. We have recently found that leukocyte-derived hypochlorous acid is able to react with the nitric-oxide synthase (NOS) substrate L-arginine to produce chlorinated L-arginine (cl-L-Arg). Interestingly, cl-L-Arg potently inhibits the formation of NO metabolites in cultured endothelial cells. It is unknown whether cl-L-Arg has a direct inhibitory effect on endothelial NOS (eNOS). In addition, the effect of cl-L-Arg on the other NOS isoforms, neuronal NOS (nNOS) and inducible NOS (iNOS), is also unknown. Therefore, we designed the current study to test the effects of cl-L-Arg on eNOS, nNOS, and iNOS. Using recombinant NOS, we found that cl-L-Arg had a direct inhibitory effect on the activity of NOS. The effect of cl-L-Arg on NOS activity is nonselective, as all three NOS isoforms were inhibited with a similar IC(50). We further determined the effect of cl-L-Arg on the three NOS isoforms at the tissue level. The results demonstrated that cl-L-Arg potently inhibited all three NOS isoform-mediated vessel reactivities, as well as the NOS signaling molecule cGMP. Cl-L-Arg might serve as a novel endogenous NOS inhibitor and an important mediator for vascular dysfunction under inflammatory conditions such as atherosclerosis. Blocking cl-L-Arg formation may be a new therapeutic approach to cardiovascular diseases.
Yang
Jian
J
Vascular Biology Center, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Ji
Ruirui
R
Cheng
Yunhui
Y
Sun
Ju-Zhong
JZ
Jennings
Lisa K
LK
Zhang
Chunxiang
C
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D006152:Cyclic GMP / Q000032:analysis; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006997:Hypochlorous Acid / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; C018524:N,N-dimethylarginine; D006997:Hypochlorous Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP