International Journal of Hypertension / 2012 / Article / Fig 1

Review Article

Novel Insights into the Vasoprotective Role of Heme Oxygenase-1

Figure 1

Exposure of endothelial cells to steady laminar shear stress (LSS). (a) HUVECs (0.8 to 1 × 106 cells per glass slide) are shear stressed using a parallel plate flow chamber connected to a constant pressure drop flow loop, maintained at 37°C and gassed continuously with a humidified mixture of 5% CO2 in air. Endothelial monolayers are continuously perfused in a closed circuit at an estimated shear stress of 10 dyn/cm2 (flow rate of 2.53 mL/min; shear rate of 1400 sec−1) with 7 mL of perfusion DMEM-medium199 (50% vol/vol), supplemented with 5% fetal calf serum, 1% glutamine, and antibiotics for 6 hours [11]. (b) In HUVEC, steady LSS activates cPLA2, thus releasing free arachidonic acid (AA) from cell membrane phospholipids, the substrate of cyclooxygenase isoenzymes (COX-1 and COX-2). In addition, LSS upregulates COX-2 expression in HUVEC, without affecting the expression of COX-1 and downstream synthases (such as cPGES, mPGES2, PGIS, LPGDS, PGFS) [11]. Both COX-1 and COX-2 participate in the biosynthesis of PGE2, PGI2, PGD2, and PGF2α as suggested by the finding that aspirin (a nonselective COX inhibitor) affects the levels of all these prostanoids. Differently, the selective COX-2 inhibitor (NS-398) affected only PGI2 in HUVECs exposed to LSS which overexpressed COX-2. COX-2-dependent PGI2, induced by LSS, through the interaction with a specific receptor (IP), causes the induction of HO-1. It constrains TNF-α biosynthesis in HUVECs under this experimental condition. In fact, LSS-dependent reduction of TNF-α generation is completely countered by the selective COX-2 inhibitor NS-398, the nonselective COX inhibitor aspirin, or the specific PGI2 receptor (IP) antagonist RO3244794 [11, 12]. Finally, by the use of the novel imidazole-based HO-1 inhibitor QC15 [13], it has been shown that HO-1 induction in response to COX-dependent PGI2 plays a role in LSS-dependent reduction of TNF-α biosynthesis [11].
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