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NDT Advance Access originally published online on March 26, 2007
Nephrology Dialysis Transplantation 2007 22(6):1495-1499; doi:10.1093/ndt/gfm093
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Nathalie Hill-Kapturczak and Anupam Agarwal

Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA

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{at}uab.edu

Keywords: acute renal injury; atherosclerosis; haem oxygenase; vascular neointimal proliferation



   The haem oxygenase (HO) enzyme system
Top
 The haem oxygenase (HO)...
HO-1 and vascular injury
 HO-1 and atherosclerosis
 HO-1, hypertension and...
 HO-1 as a potent...
 Summary
 References
 
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 (<5-fold) of HO-1 expression are protective, whereas high 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.



   HO-1 and vascular injury
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 The haem oxygenase (HO)...
 HO-1 and vascular injury
HO-1 and atherosclerosis
 HO-1, hypertension and...
 HO-1 as a potent...
 Summary
 References
 
HO-1 is not only up-regulated following balloon-induced vascular injury, but also reduces neointimal proliferation and vascular restenosis. These results are supported by findings showing that chemical inducers or adenoviral gene delivery of HO-1 to the vasculature reverses vascular neointimal proliferation, effects that are blocked by inhibitors of HO enzyme activity [5,20–22]. Furthermore, products of the HO reaction, CO, biliverdin and bilirubin, have been shown to suppress neointimal proliferation in an arterialized vein graft model and balloon injury model in rats and pigs [23–25]. The mechanism underlying this effect is related to increased apoptosis and decreased proliferation of smooth muscle cells by HO-1-derived products as well as upregulation of the cell cycle inhibitory protein, p21 [11]. Recent studies have linked the vascular protective effects of drug-coated stents (e.g. rapamycin, paclitaxel) to HO-1 induction. Both rapamycin and paclitaxel are potent HO-1 inducers and in the absence of HO-1, are not capable of inhibiting smooth muscle cell proliferation [26–28]. These observations are strengthened by studies evaluating patients with HO-1 gene microsatellite polymorphisms involving a (GT)n repeat region in the proximal promoter, length variations of which correlate with HO-1 induction and are associated with more or less significant vascular disease (reviewed in [29]). A recent study showed that in haemodialysis patients, those with longer (GT)n repeats (>30) had a higher frequency of failure of their vascular access and poor patency of arteriovenous fistulae compared to those with <30 (GT)n repeats [30]. Hence, evidence thus far supports a protective role for HO-1 in vascular injury models.



   HO-1 and atherosclerosis
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 The haem oxygenase (HO)...
 HO-1 and vascular injury
 HO-1 and atherosclerosis
HO-1, hypertension and...
 HO-1 as a potent...
 Summary
 References
 
HO-1 mRNA and protein is also abundant in animal and human atherosclerotic plaques and is expressed throughout the development of atherosclerotic lesions, from early fatty streak to the advanced complex atherosclerotic lesion (reviewed in [5]). Proatherogenic agents such as lipid metabolites, proinflammatory cytokines, peroxynitrite and haem have been shown to induce HO-1, and more importantly, HO-1 induction and its activity is protective in animal models of atherosclerosis. Upregulation of HO-1 by hemin, a potent inducer as well as a substrate for HO-1, attenuated atherosclerosis, whereas inhibition of HO enzyme activity using tin protoporphyrin accelerated lesion formation in LDL-receptor knockout mice and Watanabe heritable hyperlipidemic rabbits [31–32]. The development of atherosclerosis in apolipoprotein E (apoE)-deficient mice was also attenuated by administration of an adenoviral HO-1 vector [33]. Furthermore, HO-1–/–apoE–/– double knockout mice have accelerated and more advanced atherosclerotic lesion formation compared to apoE–/– mice [34]. It should also be noted that vascular endothelial cells and smooth muscle cells derived from HO-1 knockout mice are more sensitive to oxidized lipid-induced cell injury [35] and are more susceptible to oxidant stress [34] than wild-type cells. Further underscoring the cytoprotective potential of HO-1 in atherosclerosis, Bach1 knockout mice (Bach1 is a transcriptional repressor of HO-1) have increased myocardial HO-1 expression and are resistant to ischaemic and pro-atherosclerotic stresses [36,37]. In contrast, an HO-1 deficient human patient presented with intravascular haemolysis and prominent endothelial cell injury; fatty streaks and fibrous plaques in the aorta were noted at autopsy in this 6-year old child [38,39]. HO-1 also attenuates the vascular neointimal lesions seen in transplant-related arteriosclerosis [40]. Recent studies have shown that lipid-lowering agents such as statins and probucol exhibit potent anti-inflammatory effects via HO-1 induction [41,42]. Thus, a substantial body of evidence, using pharmacological induction/inhibition, gene delivery techniques, as well as mutant models, suggests that HO-1 confers cytoprotection in atherosclerosis.



   HO-1, hypertension and vasculature
Top
 The haem oxygenase (HO)...
 HO-1 and vascular injury
 HO-1 and atherosclerosis
 HO-1, hypertension and...
HO-1 as a potent...
 Summary
 References
 
There is evidence suggesting that the induction of HO-1 is a vasodilator response in some models of hypertension. In angiotensin II-induced systemic hypertension, HO-1 is up-regulated in the kidney and in vascular endothelial and adventitial cells (reviewed in [3]). In this model, retroviral overexpression of HO-1 or administration of hemin-attenuated hypertension in angiotensin-induced hypertension (reviewed in [3]). In spontaneously hypertensive rats (SHR), acute treatment (4 d) with inducers/substrates (tin chloride, hemin, haem L-arginate, haem L-lysinate) of HO-1 restore blood pressure (reviewed in [4]). More recently, it has been reported that the blood pressure in adult SHR is normalized for up to 9 months after continuous (only 21 days) hemin treatment via subcutaneous implanted osmotic mini-pump [43]. HO activity in general, and CO specifically, are implicated in restoring normal pressure in a model of acute hypertension in which a nitric oxide is either inhibited or scavenged to achieve hypertension [44]. CO appears to mediate vasodilator effects through activation of cGMP and Ca-activated K channels as well as inhibition of the vasoconstrictor endothelin-1 [45,46].

There have been, however, reports by Johnson and coworkers that the HO system actually impairs vascular reactivity in several animal models of systemic hypertension, including deoxycorticosterone acetate (DOCA)-salt hypertensive rat, obese Zucker rat and Dahl salt-sensitive (Dahl-S) rat models [47]. These investigators postulate that, although haem-derived CO relaxes vascular smooth muscle, it can also promote endothelium-dependent vasoconstriction by interfering with the nitric oxide system [47,48]. Indeed, they demonstrate that exogenous CO (100 µM) prevented the restoration of flow-induced dilation by an HO inhibitor metalloporphyrin in arterioles of Dahl-S rat and obese Zucker rats [47,48]. In contrast, however, Kaide et al. [49] reported that exogenous CO (10 µM) administration to rat renal interlobar arteries reduces the sensitivity of vascular smooth muscle to constrictor agonists in the presence of an HO inhibitor metalloporphyrin [49]. Perhaps the appropriate amount of CO is required for vasopressor effects, whereas too much CO poisons the haem-containing NOS, effectively eliminating endothelium-dependent vasorelaxation. Thorup et al. [50] demonstrated that low concentrations of CO (up to 100 nM) dose-dependently increases NO release, while high concentrations of CO (10 µM) inhibits NO production and eNOS activity in renal resistance arteries [50]. In vivo and in vitro studies of hypertension employing HO-1 knockout mice would potentially obviate the need of metalloporphyrin inhibitors, which have other non-specific effects, including NO synthase pathway inhibition or activation. The systematic reintroduction of the byproducts of the HO reaction would be beneficial in determining the effects and cytoprotective/detrimental amounts of the HO system in models of systemic hypertension.



   HO-1 as a potent cytoprotective enzyme or a culprit in renal disease
Top
 The haem oxygenase (HO)...
 HO-1 and vascular injury
 HO-1 and atherosclerosis
 HO-1, hypertension and...
 HO-1 as a potent...
Summary
 References
 
HO-1 in acute kidney injury
HO-1 is up-regulated in a variety of kidney injury models, including kidney transplant rejection, acute kidney injury due to ischaemia-reperfusion and nephrotoxins, glomerulonephritis, diabetic kidney disease, urinary tract obstruction, polycystic kidney disease as well as several others (reviewed in [3]). The first evidence that HO-1 induction has a cytoprotective function in vivo was demonstrated in the kidney in the glycerol model of rhabdomyolysis by Nath et al. [51] in 1992. Since then, there have been an abundance of reports evaluating the effects of the HO system in renal and non-renal disease settings. In models of acute kidney injury, including glycerol, cisplatin, cyclosporine, maleate and potassium dichromate-induced nephropathy, HO-1 induction appears to protect against renal injury, while inhibition of HO activity worsens renal injury (reviewed in [3]). In mercuric chloride-mediated nephropathy, prior induction of HO-1 protects against renal injury from a low dose of the toxin, but is ineffective at higher doses of mercuric chloride (reviewed in [3]). In the glycerol/rhabdomyolysis model, animals in which HO-1 was induced prior to glycerol injection developed only mild renal insufficiency, while rats treated with an HO inhibitor sustained severe renal failure and had significantly increased mortality [51].

As with hypertension, however, there have been conflicting reports on the efficacy of HO-1 induction in acute ischaemic injury. Prior up-regulation of HO-1 by various inducers including glutathione depletor, haemolysate, tin chloride, and cobalt consistently rescued kidneys from ischaemia-reperfusion injury, with one exception, hemin, which exacerbated injury (reviewed in [3]). Unfortunately, the whole gambit of effects has been reported in experiments involving inhibition of HO activity by metalloporphyrins, which have been shown to worsen, have no apparent effect, and reduce renal ischaemia-reperfusion injury, depending on the study (reviewed in [3]). These variable results may at least in part reflect the experimental model, dose and timing of the intervention and potential nonspecific effects of the chemical modulators of HO enzyme activity. However, using genetically deficient HO-1 mice, the protective role of HO-1 has been clearly demonstrated in the glycerol model of rhabdomyolysis [52], renal ischaemia-reperfusion [53] and cisplatin-induced renal injury [54]. It would be of significant interest to elucidate the precise location in the kidney where HO-1 is required for its protective effects. Studies using targeted overexpression or deletion of HO-1 in the kidney, specifically to particular segments along the nephron, would provide important insights.

HO-1 in sickle cell disease (SCD)
Chronic nephropathy is a serious complication of SCD, a haemolytic disease characterized by vaso-occlusion, leading to ischaemia/reperfusion injury and organ damage. A disease in which red blood cells are destroyed, resulting in the release of the haemoglobin and hence haem, it is not surprising that HO-1 is up-regulated in the vasculature and kidney in both human and murine models of SCD [55–57]. Belcher et al. [56] recently demonstrated that increasing HO-1 expression by hemin pre-treatment of transgenic sickle mice attenuated hypoxia/reoxygenation-induced stasis of venular blood flow in the subcutaneous skin of sickle cell mice, which was also observed by biliverdin or CO treatment, while HO-1 inhibition with tin protoporphyrin amplified stasis. Conversely, it has been reported that chronic treatment of sickle mice with an HO inhibitor metalloporphyrin protected these mice from ischaemia-induced renal injury and reduced expression of injury-related genes and vascular congestion [57]. These preclinical results show great promise for the protective effects of HO inhibition with the metalloporphyrins in SCD and further testing in clinical studies. It is not known, however, if inhibition of HO activity is the sole reason for the protective effects in this scenario, as metalloporphyrin inhibitors have other non-specific effects and it would be interesting to see if re-introducing HO catabolites in this model enhance or exacerbate these effects.



   Summary
Top
 The haem oxygenase (HO)...
 HO-1 and vascular injury
 HO-1 and atherosclerosis
 HO-1, hypertension and...
 HO-1 as a potent...
 Summary
References
 
HO-1 induction has been reported in a wide range of clinical settings and it has potential beneficial as well as injurious effects, depending on many factors. As highlighted in an elegant review by Nath et al. [58], in each instance, ‘HO-1 can be a potent protectant; in others, a seemingly disinterested bystander; and in still other circumstances, a pernicious perpetrator of cellular damage’. Clearly, identification of the effects of HO-1 induction, whether good or bad in a given pathophysiological condition, holds great promise in reducing tissue pathology through manipulation of HO-1 expression and/or its byproducts.

Conflict of interest statement None declared.



   References
Top
 The haem oxygenase (HO)...
 HO-1 and vascular injury
 HO-1 and atherosclerosis
 HO-1, hypertension and...
 HO-1 as a potent...
 Summary
 References
 

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Received for publication: 18. 1.07
Accepted in revised form: 1. 2.07


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