Therapeutic Potential of Heme Oxygenase-1 in Aneurysmal Diseases

Jiang, Wei-Cheng; Chen, Chen-Mei; Hamdin, Candra Dwipayana; Orekhov, Alexander N.; Sobenin, Igor A.; Layne, Matthew D.; Yet, Shaw‐Fang

doi:10.3390/antiox9111150

Cited by 7 publications

(9 citation statements)

References 153 publications

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“…Currently, some studies have investigated novel treatment options based on the inflammatory response in aortic dissection. HOMX1 has been demonstrated to be a protective factor in cardiovascular health, and excessive vascular inflammation has been observed in HOMX1-deficient humans (58)(59)(60). Ho et al investigated the role of HOMX-1 in angiotensin IIinduced AAA formation in HO-1+/+apoE-/-and HO-1-/-apoE-/-mice and demonstrated the essential roles of HOMX-1 in suppressing the pathogenesis of abdominal aortic aneurysm (61).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Hub Genes and the Mechanism of Immune Infiltration in Stanford Type a Aortic Dissection

Gao

Sun

Liu

et al. 2021

Front. Cardiovasc. Med.

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Background: Stanford type A aortic dissection (AAD) is a catastrophic disease. An immune infiltrate has been found within the aortic wall of dissected aortic specimens. The recall and activation of macrophages are key events in the early phases of AAD. Herein, the immune filtration profile of AAD was uncovered.Methods: Gene expression data from the GSE52093, GSE98770 and GSE153434 datasets were downloaded from the Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) of each dataset were calculated and then integrated. A protein-protein interaction (PPI) network was established with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the hub genes were identified in Cytoscape. Furthermore, gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of hub genes were performed. Finally, we set GSE52093 and GSE98770 as the training set and GSE153434 as the validation set to assess immune infiltration in AAD using CIBERSORTx and analyzed the correlations between immune cells and hub genes in both the training and validation sets.Results: Sixty-one integrated DEGs were identified. The top 10 hub genes were selected from the PPI network, and 140 biological process (BP) terms and 12 pathways were enriched among the top 10 hub genes. The proportions of monocytes and macrophages were significantly higher in AAD tissues than in normal tissues. Notably, this result was consistent in the training set and the validation set. In addition, we found that among the hub genes, CA9, CXCL5, GDF15, VEGFA, CCL20, HMOX1, and SPP1 were positively correlated with CD14, a cell marker of monocytes, while CA9, CXCL5, GDF15, and VEGFA were positively correlated with CD68, a cell marker of macrophages in the training set. Finally, according to the results of the GO and KEGG analysis of hub genes, we found that the monocyte/macrophage-related genes were involved in immune-inflammatory responses through degradation of the extracellular matrix, endothelial cell apoptosis, hypoxia and the interaction of cytokines and chemokines.Conclusion: The monocyte-macrophage system plays a major role in immune-inflammatory responses in the development of AAD. Several hub genes are involved in this process via diverse mechanisms.

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Section: Discussionmentioning

confidence: 99%

Analysis of Hub Genes and the Mechanism of Immune Infiltration in Stanford Type a Aortic Dissection

Gao

Sun

Liu

et al. 2021

Front. Cardiovasc. Med.

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“…Both models suggest that lack of HO-1 exacerbates AAA formation. In accordance, the relevance of HO-1 in AAA biology was addressed using HO-1 modulators, and the HO-1 upregulation was concomitant with a positive impact on AAA [reviewed in [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

A Dual Role of Heme Oxygenase-1 in Angiotensin II-Induced Abdominal Aortic Aneurysm in the Normolipidemic Mice

Kopacz

Klóska

Werner

et al. 2021

Cells

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Abdominal aortic aneurysm (AAA) bears a high risk of rupture and sudden death of the patient. The pathogenic mechanisms of AAA remain elusive, and surgical intervention represents the only treatment option. Heme oxygenase-1 (HO-1), a heme degrading enzyme, is induced in AAA, both in mice and humans. HO-1 was reported to mitigate AAA development in an angiotensin II (AngII)-induced model of AAA in hyperlipidemic ApoE-/- mice. Since the role of hyperlipidaemia in the pathogenesis of AAA remains controversial, we aimed to evaluate the significance of HO-1 in the development and progression of AAA in normolipidemic animals. The experiments were performed in HO-1-deficient mice and their wild-type counterparts. We demonstrated in non-hypercholesterolemic mice that the high-dose of AngII leads to the efficient formation of AAA, which is attenuated by HO-1 deficiency. Yet, if formed, they are significantly more prone to rupture upon HO-1 shortage. Differential susceptibility to AAA formation does not rely on enhanced inflammatory response or oxidative stress. AAA-resistant mice are characterized by an increase in regulators of aortic remodeling and angiotensin receptor-2 expression, significant medial thickening, and delayed blood pressure elevation in response to AngII. To conclude, we unveil a dual role of HO-1 deficiency in AAA in normolipidemic mice, where it protects against AAA development, but exacerbates the state of formed AAA.

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“…The development of such modifications disrupts the aortic wall, making the aorta vulnerable to hemodynamic injury [ 23 , 24 ]. Apart from mutations in the fibrillin-1 gene, also changes within transforming growth factor β receptor 2 (TGF-βR2) and TGF-βR1, which regulate extracellular matrix synthesis and homeostasis, can cause Marfan’s syndrome [ 25 , 26 , 27 ]. According to estimations, up to 5% of MFS patients are carriers of the mutation in the TGF-βR2 gene [ 28 ].…”

Section: Marfan’s Syndrome (Mfs)mentioning

confidence: 99%

“…Recently, some studies have suggested the protective function of heme oxygenase-1 (HO-1) in the abdominal aortic aneurysm (AAA). Heme oxygenase-1 is a stress response protein that plays an essential role in the protection against injury since it possesses antioxidative and anti-inflammatory properties [ 27 ]. Its utility has been previously studied in cardiovascular diseases [ 126 , 127 ].…”

Section: Oxidative Stress-reducing Strategiesmentioning

confidence: 99%

“…The results of studies carried out on an animal model (haplo-insufficient HO-1 mice) revealed that such animals were more prone to elastase-induced AAA compared to wild-type mice [ 128 ]. In turn, Jiang et al [ 27 ] showed that HO-1 expression was critical for AAA growth and severity. Moreover, lack of HO-1 was found to increase the prevalence of AAA and the risk of its rupture in the angiotensin II-induced AAA model [ 129 ].…”

Section: Oxidative Stress-reducing Strategiesmentioning

confidence: 99%

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Oxidative Stress-Related Susceptibility to Aneurysm in Marfan’s Syndrome

et al. 2021

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The involvement of highly reactive oxygen-derived free radicals (ROS) in the genesis and progression of various cardiovascular diseases, including arrhythmias, aortic dilatation, aortic dissection, left ventricular hypertrophy, coronary arterial disease and congestive heart failure, is well-established. It has also been suggested that ROS may play a role in aortic aneurysm formation in patients with Marfan’s syndrome (MFS). This syndrome is a multisystem disorder with manifestations including cardiovascular, skeletal, pulmonary and ocular systems, however, aortic aneurysm and dissection are still the most life-threatening manifestations of MFS. In this review, we will concentrate on the impact of oxidative stress on aneurysm formation in patients with MFS as well as on possible beneficial effects of some agents with antioxidant properties. Mechanisms responsible for oxidative stress in the MFS model involve a decreased expression of superoxide dismutase (SOD) as well as enhanced expression of NAD(P)H oxidase, inducible nitric oxide synthase (iNOS) and xanthine oxidase. The results of studies have indicated that reactive oxygen species may be involved in smooth muscle cell phenotype switching and apoptosis as well as matrix metalloproteinase activation, resulting in extracellular matrix (ECM) remodeling. The progression of the thoracic aortic aneurysm was suggested to be associated with markedly impaired aortic contractile function and decreased nitric oxide-mediated endothelial-dependent relaxation.

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Therapeutic Potential of Heme Oxygenase-1 in Aneurysmal Diseases

Cited by 7 publications

References 153 publications

Analysis of Hub Genes and the Mechanism of Immune Infiltration in Stanford Type a Aortic Dissection

Analysis of Hub Genes and the Mechanism of Immune Infiltration in Stanford Type a Aortic Dissection

A Dual Role of Heme Oxygenase-1 in Angiotensin II-Induced Abdominal Aortic Aneurysm in the Normolipidemic Mice

Oxidative Stress-Related Susceptibility to Aneurysm in Marfan’s Syndrome

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