Protein kinase C inhibitors prevent impairment of endothelium-dependent relaxation by oxidatively modified LDL.
The mechanism(s) of inhibition of endothelium-dependent relaxation (EDR) by oxidized low-density lipoprotein (Ox-LDL) was examined in isolated porcine coronary arteries and rabbit aortas. Incubation with Ox-LDL but not native LDL caused the inhibition of thrombin- or acetylcholine-induced EDR, whereas A23187-induced EDR was preserved after incubation with Ox-LDL. Lysophosphatidylcholine (lysoPC), which was abundant in Ox-LDL and was found to be transferred from Ox-LDL to endothelial cells, also caused the inhibition of EDR in response to thrombin or acetylcholine but not to A23187. Ox-LDL depleted of lysoPC, which was prepared by phospholipase B, failed to inhibit the vasorelaxation. Coincubation with staurosporine or calphostin C, potent inhibitors of protein kinase C, attenuated the EDR inhibition by Ox-LDL or lysoPC. Phorbol 12-myristate 13-acetate, a specific protein kinase C activator, caused the EDR inhibition, and its effect was attenuated by staurosporine or calphostin C. Furthermore, lysoPC was capable of activating protein kinase C purified from cultured porcine endothelial cells. In conclusion, protein kinase C activation plays a role in the inhibition of surface receptor-mediated EDR by Ox-LDL, and lysoPC transferred from Ox-LDL to endothelial cells may be involved in the activation of protein kinase C.
Division of Cardiology, Kumamoto University School of Medicine, Japan.
M
M
Ohgushi
K
K
Kugiyama
K
K
Fukunaga
T
T
Murohara
S
S
Sugiyama
E
E
Miyamoto
H
H
Yasue
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001158:Arteries / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D011493:Protein Kinase C