COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

Abstract

High levels of prostacyclin (PGI2; measured as 6-keto-PGF1alpha) have been reported in patients under septic shock. Because this was at variance with our previous findings of nitration and inhibition of PGI2 synthase by endotoxin (LPS) in the endothelium, we examined the role of vascular smooth muscle as an alternative source of PGI2. Bovine aortic smooth muscle cells (SMC) in passage 1 contained high levels of PGI2 synthase but no activity and no detectable levels of COX-1 or COX-2. LPS exposure for 3 h caused COX-2 mRNA and protein levels to rise during 8 h together with a large increase in PGI2 synthase activity. In contrast, cytokines lead to only a moderate increase of both PGI2 and PGE2. Specific COX-2 inhibitors completely blocked PGI2 formation but PGE2 synthesis only partially. Unexpectedly, *NO formation remained low over 6-8 h, which may be a reason for the lack of nitration and inhibition of prostacyclin synthase in LPS exposed SMC. Our results can explain the clinical observation of severe hypotension in progressive stages of septic shock as a mechanism to compensate endothelial dysfunction. According to our data, the use of COX-2-specific inhibitors may not be advisable in septic patients. In contrast, administration of COX-1-specific blockers could prevent platelet aggregation during progressed stages of endotoxic shock.

Activation of the PGI 2 /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

“…21 In this context, it has been shown that VSMCs are also able to produce PGI 2 in a COX-2-dependent manner in response to LPS. 10 Thus, it seems likely that the strong rise in 6-keto-PGF 1␣ plasma levels observed in our in vivo study may be the result of an induction of COX-2 leading to increased levels of PGI 2 . In line with this, it has been found that inhibition of COX-2 improves vascular endothelial dysfunction induced by LPS.…”

“…Recent evidence suggests that the inducible isoform of COX, COX-2, is the main responsible enzyme for the increased production of PGI 2 in VSMCs. 10,11 In line with this, it has been shown that inhibition of COX-2 attenuates the fall in blood pressure or improves vascular endothelial dysfunction in endotoxemic animals. 12,13 Therefore, we hypothesized that the PGI 2 /IP system could especially contribute to the development of LPS-induced septic shock.…”

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

“…Interestingly, the peroxide tone for the two PGHS isoenzymes was reported to be 21nM for PGHS-1 but only 2nM for PGHS-2 [13]. With some exceptions, inducible PGHS-2 is usually expressed under diverse pathological conditions, which are mostly associated with an increased formation of oxidants [14]. Unlike PGHS-2, PGHS-1 is constitutively expressed in both platelets and in numerous other cell types.…”

Low-dose acetylsalicylic acid inhibits the secretion of interleukin-6 from white adipose tissue

“…In our study, endogenous adipose PGE 2 synthesis and secretion were unrelated to IL-6. However, given that both COX isoforms are constitutively expressed, these data suggest that in this tissue, as in endothelial and smooth muscle cells, 34 prostacyclin synthesis is more coupled to COX-2 activity and drives the IL-6 secretion.…”