Association of HO-1 (GT)n Promoter Polymorphism and Cardiovascular Disease: A Reanalysis of the Literature

Daenen, Kristien; Martens, Pieter; Bammens, Bert

doi:10.1016/j.cjca.2015.06.006

Cited by 26 publications

(25 citation statements)

References 42 publications

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“…Importantly, the findings in animal models are in accordance with several clinical investigations, since in humans HMOX1 gene expression is modulated by a guanidine thymidine dinucleotide ([GT]n) repeat polymorphism in the promoter region (reviewed in: [8]). Shorter repeats with (GT)n <25 are associated with higher inducibility and activity of HMOX1.…”

Section: Introductionsupporting

confidence: 80%

“…Shorter repeats with (GT)n <25 are associated with higher inducibility and activity of HMOX1. On the other hand, the longer repeats result in lower HMOX1 expression and activity and were associated with an increased risk of cardiovascular disease (reviewed in: [8]). Thus, heme oxygenase-1 is important for cardioprotection and repair, but its involvement in the suppression of post-ischemic inflammation remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

et al. 2017

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Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1−/−) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1−/− mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1−/− than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1−/− mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1−/− mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1−/− mice.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0629-y) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

et al. 2017

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“…133–135 However, more elaborate recent meta-analysess were performed to address this issue, and after careful review of the literature and accounting for various methods of randomization, the authors have corroborated the protective effects of HO-1 promoter polymorphisms. 121, 122 Furthermore, these studies identified potential confounding factors, such as age, race, gender and preexisting conditions/risk factors, that need to be accounted for during design and interpretation of these studies. In this age of precision medicine, taking these factors into consideration would potentially enable a more personalized approach to patients.…”

Section: Recent Advancesmentioning

confidence: 99%

Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury

Bolisetty

Zarjou

Agarwal

2017

American Journal of Kidney Diseases

116

114

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A common clinical condition, acute kidney injury (AKI) significantly influences morbidity and mortality, particularly in critically ill patients. The pathophysiology of AKI is complex and involves multiple pathways including inflammation, autophagy, cell cycle progression, and oxidative stress. Recent evidence suggests that a single insult to the kidney significantly enhances the propensity to develop chronic kidney disease. Therefore, generation of effective therapies against AKI are timely. In this context, the cytoprotective effects of heme oxygenase 1 (HO-1) in animal models of AKI are well documented. HO-1 modulates oxidative stress, autophagy, and inflammation, and regulates the progression of cell cycle via direct and indirect mechanisms. These beneficial effects of HO-1 induction during AKI are, in part, mediated by the by-products of the HO reaction (iron, carbon monoxide, and bile pigments). This review highlights the recent advances in the molecular mechanisms of HO-1–mediated cytoprotection and discusses the translational potential of HO-1 induction in AKI.

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“…Nrf2 recognizes specific DNA-binding elements of the HO-1 promoter (31–33). This study showed that cholesterol stimulation induced the upregulation of Nrf2 expression in cardiomyocytes, and then caused the upregulation of HO-1 expression.…”

Section: Discussionmentioning

confidence: 99%

HO-1/EBP interaction alleviates cholesterol-induced hypoxia through the activation of the AKT and Nrf2/mTOR pathways and inhibition of carbohydrate metabolism in cardiomyocytes

Jin

Cao

et al. 2017

International Journal of Molecular Medicine

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Heme oxygenase-1 (HO-1) is an inducible and cytoprotective enzyme that provides a defense against oxidant damage. The present study screened 137 HO-1/interacting proteins using a profound co-immunoprecipitation (Co-IP) coupled with proteomics, and profiled the global HO-1 interactome network, including oxidative phosphorylation, endoplasmic reticulum and transport vesicle functions. Among these molecules, we observed that a novel interactor, emopamil-binding protein (EBP), is closely related to the cholesterol metabolism process. This study demonstrated that cholesterol promotes excessive oxidative stress and alters the energy metabolism in cardiomyocytes, further triggering numerous cardiovascular diseases. We observed that cholesterol caused the overexpression of EBP and HO-1 by the activation of AKT and Nrf2/mTOR pathways. In addition, HO-1 and EBP performed a myocardial protective function. The overexpression of HO-1 alleviated the cholesterol-induced excessive oxidative stress status by inhibition of the carbohydrate metabolism. Notably, we also confirmed that the loss of partial HO-1 activity aggravated the oxidative damage and cardiac systolic function induced by a high-fat diet in HO-1 heterozygous (HO-1+/−) mice. These findings indicate that the HO-1/EBP interaction plays a protective role in alleviating the dysfunction of oxidative stress and cardiac systolic function induced by cholesterol stimulation.

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Association of HO-1 (GT)n Promoter Polymorphism and Cardiovascular Disease: A Reanalysis of the Literature

Cited by 26 publications

References 42 publications

Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury

HO-1/EBP interaction alleviates cholesterol-induced hypoxia through the activation of the AKT and Nrf2/mTOR pathways and inhibition of carbohydrate metabolism in cardiomyocytes

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