Lysophosphatidylcholine inhibits relaxation of rabbit abdominal aorta mediated by endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor independent of protein kinase C activation.

Abstract

Hypercholesterolemia is associated with increased oxidized LDL and impaired endothelium-dependent relaxation (EDR). An inhibitory component of oxidized LDL is lysophosphatidylcholine (LPC). To determine the effect and mechanism(s) of action of LPC on EDR mediated by endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF), rabbit abdominal aortic rings were suspended for measurement of isometric tension and studied under three conditions: control; with 25 mmol/L K+ buffer to isolate relaxation mediated by EDNO; and in rings treated with N omega-nitro-L-arginine methyl ester (L-NAME, 30 mumol/L) to isolate relaxation mediated by EDHF. Incubation with LPC (10 and 30 mumol/L) for 30 minutes inhibited EDR in a concentration-dependent manner. LPC (30 mumol/L) significantly inhibited maximal relaxation to acetylcholine in control, 25 mmol/L K(+)-, and L-NAME-treated rings (77.1 +/- 7.8%, 42.1 +/- 8.9%, and 3.4 +/- 7.7%) compared with untreated rings (99.0 +/- 0.9%, 90.9 +/- 2.2%, and 54.7 +/- 4.7%, P < .05). Inhibition of relaxation was specific to endothelium-dependent responses in that relaxation to direct smooth muscle vasodilators (papaverine, 8-bromo-cGMP, and sodium nitroprusside) were unaltered by LPC. The inhibition by LPC (30 mumol/L) was not due to cytotoxicity, because EDR returned to normal levels after repeated washing with physiological salt solution containing 0.1% albumin. Co-incubation with protein kinase C inhibitors, staurosporine (20 nmol/L) or calphostin C (1 mumol/L), had no effect on the EDR inhibition by LPC (30 mumol/L). Furthermore, LPC continued to inhibit EDR in rings in which protein kinase C was down-regulated by incubation for 18 hours with 1 mumol/L phorbol 12-myristate 13-acetate (PMA).(ABSTRACT TRUNCATED AT 250 WORDS)