Haem oxygenase-1--a culprit in vascular and renal damage?

Abstract

The haem oxygenase (HO) system is responsible for the catabolism of free haem, a potent pro-oxidant, released during the normal and pathophysiological breakdown of haem-containing proteins. HO degrades haem releasing biliverdin, iron and carbon monoxide (CO) [1]. Biliverdin is converted to bilirubin by biliverdin reductase. There are two well characterized isoforms of active HO: an inducible enzyme, HO-1, and a constitutive isoform, HO-2. They are products of different genes with dissimilar regulation and tissue distribution (reviewed in [2]). HO-1 is a 32 kDa protein that is highly inducible in mammalian tissues by a wide variety of stimuli including haem, heavy metals, growth factors, nitric oxide (NO), peroxynitrite, modified lipids, hypoxia, hyperoxia, cytokines as well as others. HO-2 is a 36 kDa protein that is constitutively expressed in distinct locations including in the brain, endothelium, testis and distal nephron segments (reviewed in [2]). The products of HO-mediated haem degradation (biliverdin, bilirubin, carbon monoxide, ferrous iron) regulate important biological processes, including oxidative stress, inflammation, apoptosis, cell proliferation, angiogenesis and fibrosis, through one or more of these products. The HO field has attracted numerous investigators and there has been an exponential increase in the number of publications on this enzyme ( 5–10 in 1990, to 500 in 2006). Several recent reviews and editorials have highlighted the biological effects of the reaction product(s) and the importance of HO-1 as a potent cytoprotective enzyme in diverse conditions [2–5]. HO activity, however, may not be protective in all instances [6–7]. Each of the products of the HO reaction has potential detrimental effects. Bilirubin can be toxic to neural and non-neural cells at high concentrations, and hyperbilirubinemia is responsible for diseases such as neonatal jaundice, kernicterus, and bilirubin encephalopathy [8]. CO can stimulate mitochondrial generation of free radicals and poison haem proteins [9] and ferrous iron can catalyse free radical reactions [10]. Suttner and Dennery [7], using a tetracycline regulatable system, demonstrated that low levels ( 15-fold) of overexpression actually worsen cell injury caused by hyperoxia in hamster fibroblasts. Thus, optimal levels of HO-1 induction may be required for cytoprotective benefits of HO-1. Whether similar effects related to the level of HO-1 enzyme activity occur in the kidney or vasculature is not known. HO activity may have different effects depending on the cell type and/or environment. It has been demonstrated that HO-1 inhibits the growth of renal tubular epithelial cells, increases endothelial cell cycle progression and formation of capillary-like structures in a 2D Matrigel assay, while inhibiting cell cycle progression and inducing apoptosis of smooth muscle cells [11–14]. Recent in vivo studies demonstrate that HO-1 expression and activity promotes vascular endothelial growth factor (VEGF)-mediated endothelial activation and ensuing angiogenesis, but in contrast, it inhibits lipopolysaccharide-mediated leucocyte invasion and prevents subsequent inflammatory angiogenesis (reviewed in [15]). There is also emerging evidence that HO activity may play a role in the development and/or exacerbation of some tissue pathologies. For example, increased HO activity accelerates tumour angiogenesis [16] and renders tumour cells relatively resistant to anticancer treatment [17,18]. There are several diseases associated with increased HO-1 expression including atherosclerosis, hypertension, transplant rejection, acute renal failure, glomerulonephritis and many others (reviewed in [19]). This review will highlight the specific role of HO-1 in vascular and renal injury. Correspondence and offprint requests to: Anupam Agarwal, MD, Division of Nephrology, ZRB 614, University of Alabama at Birmingham, 703 19th street south, Birmingham, AL 35294, USA. Email: agarwal@uab.edu Nephrol Dial Transplant (2007) 22: 1495–1499