Novel Insights into the Vasoprotective Role of Heme Oxygenase-1
Figure 2
Postulated molecular mechanism involved in the induction of HO-1 by COX-2-dependent PGI2, in endothelial cells exposed to steady laminar shear stress (LSS). In endothelial cells exposed to uniform LSS (characteristically associated with atherosclerotic lesion-protected areas), COX-2 is overexpressed [11]. PGI2, mainly produced by the combined activity of COX-2 and PGI2-synthase (PGIS), interacts with its specific receptor, IP [14]. This interaction may lead to the activation of adenylate cyclase (AC), causing an increase of intracellular levels of cyclic AMP (cAMP) and subsequently to the activation of protein kinase A (PKA) [14]. PKA may phosphorylate glycogen synthase kinase(GSK)-3 [15], causing its inactivation and the loss of the capacity to phosphorylate nuclear factor E2-related factor 2 (Nrf2) [16]. Reduced phosphorylation of Nrf2 causes its stabilization and translocation into the nucleus, where it promotes the transcription of antioxidant and phase II genes, including HO-1 [11, 17]. In addition to Nrf2, Kruppel-like factor(KLF)-2 is increased in endothelial cells exposed to LSS [18]. KLF2 enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation [19]. The synergistic activity of these two transcription factors forms a major contribution to the shear-stress-elicited transcriptome in endothelial cells. The overexpression of HO-1 in endothelial cells by LSS exerts an anti-inflammatory action through its capacity to inhibit the biosynthesis and release of TNF-α [11].
