Search

Heme oxygenase (HO) is a microsomal enzyme that oxidatively cleaves heme to form biliverdin, with the release of iron and carbon monoxide (CO). HO not only controls the availability of heme for the synthesis of heme proteins but also is responsible for the generation of CO, which binds to the heme moiety of heme proteins thus affecting their enzymatic activity. Cyclooxygenase (COX) is a heme protein that catalyzes the conversion of arachidonic acid to prostaglandin H(2), the precursor of prostanoids that participate in the regulation of vascular function. The goal of the present study was to determine whether the heme-HO system regulates COX enzyme expression and activity in vascular endothelial cells. Endothelial cells stably transfected with the human HO-1 gene exhibited a severalfold increase in human HO-1 mRNA levels, which was accompanied by an increase in HO activity and a marked decrease in prostaglandin (PG) E(2) and 6-keto-PGF(1alpha) levels. Exposure of cells to CoCl(2), an inducer of HO-1 gene expression, resulted in increases in HO-1 protein levels and HO activity. The increase in HO activity was associated with a subsequent decrease in COX activity, which returned to normal levels following normalization of HO activity. The addition of heme resulted in an increase in COX activity with an increase in PGE(2) and 6-keto-PGF(1alpha) levels. The degree of HO-1 expression and, consequently, the level of cellular heme, were directly related to COX activity. These results demonstrate that the heme-HO system can function as a cellular regulator of the expression of vascular COX, thus influencing the generation of prostanoids, PGE(2) and PGI(2), known to play a role in vascular homeostasis.

Publisher Summary This chapter explains a new prostaglandin pathway distinct from that which forms PGE2 and PGF2α, now referred to as the “prostacyclin pathway.” The formal naming of products in the prostaglandin family is based on the prostanoic acid skeleton. The prostacyclins are no exception. Thus, the bicyclic product now known as “prostacyclin” was referred to initially as “6(9)oxy-11,15-dihydroxy prosta-5,13-dienoic acid” and subsequently when the stereochemical assignment of the double bonds was established as 9-deoxy-6,9α-epoxy-11,15-dihydroxyprosta-5Z, 13E-dienoic acid. Prostacyclin is generally referred to the product derived from arachidonic acid; consistent with the alphabetic naming of prostaglandins, this product has been assigned the abbreviated form PGI2. While prostaglandins are derived from all cis essential fatty acids having 3, 4 and 5 double bonds, a cis double bond at carbon 5 of the fatty acid is essential for prostacyclin synthesis from the precursor endoperoxide. A factor with biological properties similar to PGI2 is spontaneously released by the lungs. This release can be enhanced by Angiotensin I and II but not by norepinephrine or vasopressin.