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Circulation on the atherosclerotic impact of heme oxygenase 1 (HO-1).

Heme oxygenase 1 determines atherosclerotic lesion progression into a vulnerable plaque. Circulation. 2009;119(23):3017-27

Interview of authors of "Heme oxygenase 1 determines atherosclerotic lesion progression into a vulnerable plaque. "

Basic Sciences, Pharmacology, Genomics and Cardiovascular Pathology

Q: Dr. Duckers, you and your colleagues just published a great article in Circulation on the atherosclerotic impact of heme oxygenase 1 (HO-1). What exactly are the key messages from your report?

A: We screened previously for genes involved in embryonic vasculogenesis in mouse and zebrafish development, and found some interesting candidates that previous were not considered. From there, we analyzed the involvement in these genes in various pathologies related to neovascularization, including plaque destabilization.
Hmox-1 was one of the candidate gene that we were able to identify during mouse embryogenesis and indeed this gene is also involved in neovessel formation in the adult animal. Remarkably silencing of the Hmox1 gene also resulted in plaque destabilization.,, whereas induction of Hmox 1 expression by adenoviral vector mediated gene transfer or
induction by local heme deposition led to plaque stabilization. During this process Hmox 1induces neovasculature in the plaque with less vascular leakage.

Q: Indeed, just as your study starts out with carotid endarterectomy samples, there has been the notion of an increase in the expression of HO-1 with disease progression and vulnerable plaque features. Based on the results of association studies, one might be tempted to conclude that it contributes to atherosclerosis and possibly even to its acute complications. Yet, your study clearly shows that it has quite the opposite effect and highlights very nicely the need for additional experiments to truly define the role of protein in the pathophysiology of atherosclerosis. What it your opinion on how this will shape future research in the field? How feasible and financeable will this be?

A: Indeed, the question arises, with the current genome wide analysis of various biobanks collected biomaterials, whether the upregulated gene products at hand are actually causative or compensatory in the pathogenesis. This actually redefines the involvement of the identified genes in the pathogenesis, and genes that previously were considered not involved in progression of the disease, may actually be involved in the protection and stabilization of the plaque phenotype and even proof to be clinically and therapeutically relevant.

Q:You were able to reproduce the plaque association findings in a particular mouse model. Please, tell us more about this mouse model and how is it is to establish.

A: This model was previously developed by Cheng and co-workers in the Thoraxcenter in which a tapered cast is placed around the common carotid artery of ApoE deficient mice on a western diet. This approach has some considerable advantages. First and most important, the histological appearance of the vulnerable plaque resembles the human phenotype: with lipid deposition, macrophage infiltration, decrease of vsmc content, thin fibrous cap, and even neovascularization with plaque hemorrhages. In addition, chemokines, cytokines and other enzymes involved in human plaque destabilization appeared to play a similar role in the murine equivalent mouse model. Equally important, the mouse model is a relative cost effective animal model which allows a vulnerable plaque to be develop in an isogenetic background within merely 9 weeks, in contrast to equivalent models in rabbits and pigs which require up to 12 months of high lipid feeding with staggering housing costs. For pharmacological evaluation, this particular mouse model provides a side-by-side comparison between the stable atherosclerotic plaque downstream and the unstable, vulnerable atherosclerotic plaque downstream of the cast, whereas the local aspect also permits therapeutic intervention at the luminal or peri-adventitial application of the pharmaco-therapeutic compound.

Q: The intervention models (pharmaceutical and adenoviral modulation) are also quite remarkable. As it reads, you started with the intervention at a time point when atherosclerotic lesions were present but not yet vulnerable to specifically address this transition, is this right?

A: Indeed, at 6 weeks after cast implantation the atherosclerotic lesions have not fully developed and resemble stable fibrous plaques. Following week 6, the plaques upstream of the cast, in the segment with low shear stress, begin to show prominent macrophage infiltration, vsmc loss, and increased lipid deposition, leading to a necrotic core, and to plaque hemorrhaging in advanced cases. This limited time frame renders this approach an excellent model to test pharmacological interventions to prevent progression of advanced atherosclerotic plaque lesions into a vulnerable phenotype by a process that is quite similar to the “natural” pathological process of plaque destabilization.

Q: Along these lines, the modulation of HO-1 expression and activity did not affect lesion size but the composition of plaques. Was it an alternation of the quality of vulnerable plaques or actually the development of vulnerable plaques?  

A: Previously, we and other collaborating groups were able to show that Hmox 1 induction or expression prevented atherogenesis and early plaque development. Hmox 1 is involved in IL10 signal transduction pathway and has been shown to be involved in macrophage function. In addition, Hmox 1 has been show to be involved in cGMP mediated cell survival, endothelial cell differentiation and recruitment of EPCs. The limited time frame does not permit to differentiate whether the Hmox 1 actually regresses unstable plaques into stable ones or prevents the progression into vulnerable plaque. Mores studies are now underway to make this distinction.

Q: In the paper it is mentioned that HO-1 induction or inhibition had no effect on lesion size or plaque phenotype of stable lesions. Does that indicate that HO-1 has no role in the initiation and progression stage of atherosclerosis? 

A:  Previously, we and other groups were able to show that Hmox 1 expression through sGC activated cGMP generation prevented early plaque formation in ApoE null mice on a western diet. In contrast Hmox 1 interferes with atherogenesis in early plaque formation, and does not appear to affect stable fibrous plaques within the 3 weeks time frame of the study. Currently, very little is known about the biological factors that trigger the growth of stable plaques and further studies are needed to understand the different dynamics that underlie the pathology of these type of lesions.

Q: What are then the “anti-atherosclerotic” effects of HO-1 and how are they mediated?

A:  Various working mechanisms have been associated with the Hmox 1 signaling cascade. Some have been associated with the anti oxidative properties of the generated biliverdine, whereas other have been associated with the release of ferric iron, leading to activation of heavy metal responsive elements in the promoters of various genes. We were able to associate the observed anti-inflammatory and anti-atherogenic effects of the Hmox 1 cascade, to the carbon monoxide induced conformational change of guanylyl cyclase leading to cGMP release and activation of cGMP dependent protein kinases. Alternatively, other groups have suggested that Hmox 1 may affect the redox state of the cellular milieu, whereas others have suggested modulation of p450 cytochrome activation or the NOS/NO signaling pathway. Most of the studies that we have performed have been reproduced in the presence of specific NOS inhibitors, whereas others have shown that the protein level of eNOS and iNOS remain unaffected in the studies at hand. Therefore the latter appears to be less likely. For a comprehensive overview of all these signaling cascades Hmox 1 mediated guanylyl cyclase activation and cGMP generation results in activation of various cGMP dependent protein kinases I would like to refer to an excellent review of Soares (1).

Q: Certainly, HO-1 has broad functions. What do you consider the most important effect for an anti-atherosclerotic impact?   

A: For the effect of Hmox 1 on progression to an unstable atherosclerotic plaque, both the immune modulatory and anti-apoptotic effect on local vsmcs appear to be crucial. More recent studies also emphasize the role of plaque vascularization, and plaque hemorrhagingl.

Q: In recent time, there have been several reports on the detrimental effect of hemoglobin deposition in atherosclerotic plaques, the significance of haptoglobin function, and the hemoglobin scavenger receptor, particularly for the development of vulnerable plaques. Do your findings play into this? 

A:  Indeed, studies have shown that haptoglobin and the hemoglobin scavenger receptor results in Hmox1 protein expression in macrophages, and is associated with CD163 mediated-macrophage activation. We have not performed immuno-staining for this specific marker on the humane atheroma samples. CD163 was also previously shown to be upregulated in plaques with signs of intraplaque hemorrhages (2). In our study, Hmox1 was indeed highest in the atherectomy samples with the most profound evidence of intraplaque hemorrhaging.

Q: What are the inducers of HO-1 expression in the vascular wall/atherosclerotic plaque? Which one is the most potent, which one is the most common?

A:  The Hmox family, alike the NOS family, comprises of a ubiquitous expressed family member, Hmox 2, and an inducible family member, Hmox 1. Hmox 1 expression can be induced by various conditions (1) including hypothermia, hyperthermia, heavy metals, oxidative stress, and cytokines. In case of atherogenesis and plaque destabilization, local inflammation, hemoglobin (hemoprotein) deposition and oxidative stress would probably drive local Hmox 1 expression in the atherosclerotic plaque.

Q: It appears that HO-1 is expressed in the plaque as part of a defense mechanism. Are there individual variations in its efficacy and can we tell if a patient is a good or bad “responder”?  For instance, are there any lab tests?

A: Polymorphisms have been described in the promoter region of the Hmox 1 gene affecting the expression level and response to cellular stress. Patients with a long CT repeat in the promotor domain respond poorly to oxidative stress, whereas patients with a short CT repeat respond more adequately. Patient with a long CT repeat (and a poor Hmox response) are more prone to develop neointimal hyperplasia following stent implantation. The association with plaque progression and atherosclerotic plaque burden in human CAD patients has not been established yet.

Q: How can HO-1 expression and activity be improved?

A: Hmox1 can be induced by various stimuli, and systemically can be induced by hemoproteins/ heme. However, commercial CO donors have also been synthesized.

Q: What are future research aspects in this area?

A: I am happy to say that the exciting field of Hmox biology is thriving: an average of 10-20 papers are published weekly on Hmox 1 biology and its implications. Also the field of plaque neovascularization generates some interesting insights in the (patho)biology of atherosclerotic plaque destabilisation and the need for neovascularization. Previously, the presence of a vascular bed in the atherosclerotic plaque has been associated with plaque progression and instability. The current study also suggests that for the functionality of the neovascular bed may play an interesting role in determining plaque fate.


Q: Thank you so much for your time and this stimulating discussion. If someone has further interest and questions, may he or she contact you by E-mail?  

A:Of course, more than happy to: The Email is: and our webpage of the laboratory is


(1) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003 Aug;24(8):449-55. Otterbein LE, Soares MP, Yamashita K, Bach FH.

(2) Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. Schaer CA, Schoedon G, Imhof A, Kurrer MO, Schaer DJ. Circ Res. 2006 Oct 27;99(9):943-50.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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