Heme oxygenase-1 (HO-1) is a stress-inducible enzyme which degrade heme to carbon monoxide, ferrous iron, and biliverdin, the latter converted to antioxidant bilirubin by biliverdin reductase (BvR). Experiments performed in HO-1 deficient or HO-1 overexpressing animals showed that the enzyme participates in maintaining the cellular homeostasis. It plays an important protective role in the vessel wall due to reducing oxidative injury, decreasing vascular constriction, diminishing the expression of adhesion molecules, attenuating the inflammatory response, and regulating cell proliferation or apoptosis. Effects of HO-1 are, however, strongly dependent on the level of induction – too high activity may be harmful, leading to increased sensitivity to some oxidative stimuli. Therefore, the crucial issue is to understand the consequences of HO-1 expression at the levels within the physiological range observed in human tissues.

Importantly, human HO-1 gene promoter is highly polymorphic, because of variation in the number of GT repeats, ranging from 12 to 40. On this basis, three classes of alleles can be distinguished: S (≤25), M (26-29), and L (≥30). It was shown in cells transfected with reporter plasmids that only short alleles were induced in response to oxidative stress. Moreover, several clinical reports demonstrated that the presence of short allele significantly decreased inflammatory reaction and oxidative injury in the vessel wall, leading to lower risk of cardiovascular complications in diabetic or hypercholesterolemic patients or to protection from oxidative-stress induced carcinogenesis.

We elucidated the influence of HO-1 promoter polymorphism on human endothelium. Experiments were carried out using human umbilical vein endothelial cells (HUVEC) of different genotypes, classified into three groups: S (genotypes S/S, S/M), M (genotypes M/M and S/L), and L (genotypes L/M, L/L). Promoter polymorphism significantly influenced expression of HO-1 induced by hemin, cobalt protoporphyrin-IX (CoPPIX), 15-deoxyD^12,14-prostaglandin-J₂ (15d-PGJ2) or H₂O₂. The strongest induction was detected in the S, while the lowest in the L groups. The most potent inducers were 15d-PGJ₂ and CoPPIX, which increased the level of HO-1 mRNA up to 600-fold. The same stimulants upregulated also expression of BvR, but induction was much weaker. Endothelial cells of S group displayed higher concentration of total glutathione and more favorable oxidative status determined by GSH:GSSG ratio. Accordingly, they survive better when exposed to oxidative stress. Moreover, they proliferated more efficiently in response to vascular endothelial growth factor. On the other hand, migration, formation of capillaries and productions of proinflammatory cytokines or adhesins were not significantly modified.

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1. HO-1 regulates expression of human MMP-1 and murine MMP-13 in vitro.
2. Role of HO-1 in chemically induced carcinogenesis in mice
3. Effects of heme oxygenase-1 on proliferation, cell cycle regulation and susceptibility of the primary murine fibroblasts to oxidative stress.
4. Overexpression of biliverdin reductase enhances heme oxygenase expression, activates ERK1, JNK1 and p38 kinases and ensure partial protection against cellular stress