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Stroke. 2005;36:1901-1903

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(Stroke. 2005;36:1901.)
© 2005 American Heart Association, Inc.

Original Contributions

Editorial Comment—Is Heme Oxygenase-1 a Causal Player for Plaque Stability?

Christine Espinola-Klein, MD; Stefan Blankenberg, MD Thomas Münzel, MD, FAHA

Department of Medicine II, Johannes Gutenberg University, Mainz, Germany


Key Words: atherosclerosis • carotid arteries • infection • inflammation • stroke

Inflammatory mechanisms play an important role in all stages of the atherosclerotic process.1 Various studies implicate that certain infectious agents represent candidates that trigger these inflammatory responses.2 An association of viral infection with atherosclerosis was first reported in the 1970s, when experimental infection of germ-free chickens with an avian herpes virus was found to produce arterial disease.3 Although several infectious pathogens have been detected within the atherosclerotic plaque, including Chlamydia pneumoniae, Cytomegalovirus, and Helicobacter pylori, the precise role of these pathogens in causing atherosclerosis or in aggravating the atherosclerotic process remains to be established.4 In addition, a pathogen resident in an atherosclerotic vessel wall may be just an "innocent bystander" rather than a causally relevant agent, and atherosclerotic arteries might be simply more susceptible to infections. Although multiple seroepidemiological studies could demonstrate associations between atherosclerosis and antibodies against different pathogens, other studies did not.2,5 More important, recent secondary prevention studies failed to prevent cardiovascular events by administering antibiotics.6,7 Because several types of pathogens may contribute to the multifaceted process of atherosclerosis, it seems to be unlikely that a single microbe causes atherosclerosis. Instead, the total pathogen burden of infection at various sites may affect atherosclerosis progression.5,8

Various mechanisms and hypotheses have been proposed to explain possible interactions between pathogen agents and the atherosclerotic vessel wall.5 These include induction of specific antibodies or alteration of circulating cytokines, acute phase proteins, and white blood cells. Results from several studies also point to a significant role of immune responses contributing to atherogenesis.5,9 One of the auto antigens discussed as a possible immune target is the heat shock protein (HSP), which is synthesized in cells exposed to inflammation, infection, or oxidative stress.9 HSP has been detected on endothelial cells, macrophages, and smooth muscle cells located in atherosclerotic plaques.9 Bacterial pathogens encoding for HSP within atherosclerotic lesions can be induced by myobacterial HSP in vitro.10 Some authors suggest that bacterial infections trigger the formation of antibodies against bacterial HSPs, which might cross-react with human HSPs within endothelial cells, thereby provoking endothelial dysfunction as the first step in the atherosclerotic process.11

H pylori is a Gram-negative microaerophile bacterium that colonizes the gastric mucosa of {approx}50% of all adults.12 It represents the major cause of chronic gastritis and peptic ulcer disease. Several investigators could show association between H pylori seropositivity and manifestations of atherosclerosis in different vascular beds, whereas other did not.13,14 H pylori has been identified within atherosclerotic plaques, and it is one of the pathogens included into the concept of pathogen burden.4,5,8 Recent publication demonstrates an association between H pylori and endothelial dysfunction.15 In experiments, an extract of H pylori has been reported to induce a disturbance of proliferation and apoptosis and to decrease the viability of cultured endothelial cells from the stomach.16 In addition, a cross-reactivity of H pylori anti-Cag antibodies with antigens of normal and atherosclerotic blood vessels has been shown.17 Moreover, H pylori infection with chronic gastritis causes malabsorption of folate and vitamins B6 and B12, followed by hyperhomocysteinemia, which is discussed as cardiovascular risk factor.12

In recent years, there has been much interest in the role of oxygen-derived free radicals and the subsequent oxidation of low-density lipoprotein (LDL) to oxidized LDL in the pathogenesis of atherosclerosis.1,18 The body has evolved a complex defense strategy to minimize the damaging effect of various oxidants, and central to this defense are the antioxidant enzymes of the blood.18–20 Heme oxygenase-1 (HO-1) was first described in 1968 and characterized in 1974 as a distinct protein entity.21,22 The products of its enzymatic reaction have important biological effects, including antioxidant, antiinflammatory, and cytoprotective functions. Three isoenzymes of HO-1 have been identified: HO-2 and HO-3, 2 constitutively expressed isoforms, and HO-1, which is inducible in most cells. HO-1 gene expression is inducible by heme, cytokines, NO donors, and conditions associated with oxidant stress. In LDL-deficient mice under high-fat diet, expression of HO-1 was increased in atherosclerotic lesion, particularly in foam cells and macrophages.23 Mice deficient in HO-1 and apolipoprotein E had more rapid progression of atherosclerosis.24 Moreover, human HO-1 deficiency leads to severe endothelial damage associated with elevations of thrombomodulin and von Willebrand factor.25 So far, multiple mechanisms of antioxidant action of HO-1 have been described. HO-1 catalyzes the rate-limiting step in heme degradation, resulting in the formation of carbon monoxide, iron, and biliverin that is subsequently reduced to bilirubin and biliverdin reductase. Bilirubin can act as potent peroxyl radical scavenger, and the reduction of leukocyte adhesion to the endothelium in the presence of oxidative stress by HO-1 induction may be explained by the antioxidant effects of bilirubin.21 Carbon monoxide has cGMP-mediated antiatherogenic effects and, in addition, inhibits cytochrome P-450, an enzyme that has been demonstrated to promote oxidative processes.21,26 Moreover, recent data showed that HO-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of NO.21,26 Thus, HO-1 represents a cellular target for NO donors and acts as an important antiatherogenetic enzyme in the vessel wall. Importantly, recent studies have demonstrated that at the shoulder region of the atherosclerotic plaques, where plaque ruptures frequently take place, large amounts of reactive oxygen species have been identified.27 Thus, an upregulation of HO-1 may point to a high degree of oxidative stress within vascular tissue or an atherosclerotic plaque and theoretically may stabilize a plaque via its antioxidant mechanisms.

In this issue of Stroke, Ameriso et al28 examined in neurologically symptomatic and asymptomatic patients plaques obtained during endarterectomy and 7 normal carotid arteries that were obtained at autopsy. The authors found that H pylori– positive specimens were present in 28 plaques, and HO-1 was expressed in 30 plaques. All 7 normal carotid arteries were negative for H pylori and HO-1. Although 82% of asymptomatic patients were positive for H pylori and 87% for HO-1, only 36% of symptomatic patients were positive for both. Therefore, the authors demonstrate that HO-1 expression is highly prevalent in asymptomatic plaques, indicating that HO-1 may indeed be able to stabilize plaques. In addition, these findings indicate that HO-1 represents a clinically relevant therapeutic target in vascular disease. It also provides indirect evidence that H pylori–induced damage may be mediated to a large extent by stimulation of the production of reactive oxygen species.

How does a H pylori infection induce oxidative stress? Oxidative damage of the stomach is one of the pathogenetic factors in chronic gastric infection with H pylori.29 H pylori is able to induce polymorphonuclear and mononuclear cells that produce large amounts of reactive oxygen species via activation of the NADPH oxidase, which could cause DNA damage to the adjacent cells, leading to gastric cancer development. In addition, H pylori induces the activation of NO pathway in macrophages and gastric endothelial cells. In the presence of reactive oxygen species such as superoxide, NO may react with superoxide to form to the highly reactive peroxynitrite.29 Peroxynitrite has been shown to induce chronic inflammation associated with point mutations and DNA damage.29 Over that, it causes endothelial dysfunction via uncoupling of the endothelial NO synthase and by causing tyrosine nitration of the prostacyclin synthase, ultimately leading to a cessation of endothelial NO and prostacyclin formation, respectively.30,31 Several antioxidative enzymes have been shown to be upregulated in the H pylori–infected gastric mucosa, including catalase, endogenous peroxidase, and superoxide dismutase in the gastric mucosa. Recently, upregulation of HO-1 has also been described as possible adaptive response to protect mucosa from oxidative injury in patients with H pylori–positive gastritis.32 Therefore, it is reasonable to conclude that similar mechanism exists in an atherosclerotic lesion in response to a local H pylori infection.

At present, H pylori is discussed to be less involved in plaque initiation rather than plaque progression and destabilization, followed by cardiovascular events including myocardial infarction and stroke. It has been suggested that chronic infections can induce a procoagulant state and thereby destabilize atherosclerotic plaques.33 In addition, it has been postulated that a persistent inflammatory response that accompanies chronic low-grade infections such as Chlamydia pneumoniae or H pylori contribute to atherosclerosis progression by increasing the concentrations of acute phase reactants such as C-reactive protein or fibrinogen.34 This could be due either to a direct action to plaques or secondary to remote signaling processes induced by these inflammatory mediators. The molecular mimicry between bacterial pathogens and human molecules may contribute to the activation of inflammation, too.5,35 Unfortunately, in the present study, neither systemic nor local markers of inflammation have been measured to prove this concept.

In conclusion, the article by Ameriso et al indicates that H pylori infection might contribute to plaque destabilization, all of which may be secondary to the induction of oxidative stress within the plaque. The simultaneously observed high prevalence of HO-1 expression in neurologically asymptomatic patients may indeed indicate that this enzyme plays a crucial role in stabilizing plaques infected with H pylori. Future research should focus on mechanisms of how H pylori is able to cause upregulation of HO-1 and whether targeting of HO-1 by drugs leading to an upregulation of this enzyme is indeed leading to a stabilization of the plaques and subsequently to fewer cardiovascular events.


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