The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. Results: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. Conclusion: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.

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Red Yeast Rice Protects Circulating Bone Marrow-Derived Proangiogenic Cells against High-Glucose-Induced Senescence and Oxidative Stress: The Role of Heme Oxygenase-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/3831750 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Jung-Tung Liu ◽

Huey-Yi Chen ◽

Wen-Chi Chen ◽

Kee-Ming Man ◽

Yung-Hsiang Chen

Keyword(s):

Oxidative Stress ◽

Bone Marrow ◽

Heme Oxygenase ◽

High Glucose ◽

Protoporphyrin Ix ◽

Vascular Complications ◽

Heme Oxygenase 1 ◽

Red Yeast Rice ◽

And Oxidative Stress

The inflammation and oxidative stress of bone marrow-derived proangiogenic cells (PACs), also named endothelial progenitor cells, triggered by hyperglycemia contributes significantly to vascular dysfunction. There is supporting evidence that the consumption of red yeast rice (RYR; Monascus purpureus-fermented rice) reduces the vascular complications of diabetes; however, the underlying mechanism remains unclear. This study aimed to elucidate the effects of RYR extract in PACs, focusing particularly on the role of a potent antioxidative enzyme, heme oxygenase-1 (HO-1). We found that treatment with RYR extract induced nuclear factor erythroid-2-related factor nuclear translocation and HO-1 mRNA and protein levels in PACs. RYR extract inhibited high-glucose-induced (30 mM) PAC senescence and the development of reactive oxygen species (ROS) in a dose-dependent manner. The HO-1 inducer cobalt protoporphyrin IX also decreased high-glucose-induced cell senescence and oxidative stress, whereas the HO-1 enzyme inhibitor zinc protoporphyrin IX and HO-1 small interfering RNA significantly reversed RYR extract-caused inhibition of senescence and reduction of oxidative stress in high-glucose-treated PACs. These results suggest that RYR extract serves as alternative and complementary medicine in the treatment of these diseases, by inducing HO-1, thereby decreasing the vascular complications of diabetes.

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ALK7 Inhibition Protects Osteoblast Cells Against High Glucose-induced ROS Production via Nrf2/HO-1 Signaling Pathway

Current Molecular Medicine ◽

10.2174/1566524021666210614144337 ◽

2021 ◽

Vol 21 ◽

Author(s):

Zhen Zhao ◽

Yu Lu ◽

Huan Wang ◽

Xiang Gu ◽

Luting Zhu ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Viability ◽

Signaling Pathway ◽

High Glucose ◽

Collagen I ◽

Cell Counting ◽

Enzyme Linked Immunosorbent Assay ◽

Heme Oxygenase 1 ◽

Ros Production ◽

Alizarin Red

Background: Some studies demonstrated that under high-glucose (HG) condition, osteoblasts develop oxidative stress, which will impair their normal functions. The effects of activin receptor-like kinase 7 (ALK7) silencing on HG-induced osteoblasts remained unclear. Objective: The aim of this study was to explore the effect of ALK7 on HG-induced osteoblasts. Methods: MC3T3-E1 cells were treated with different concentrations of HG (0, 50, 100, 200 and 300mg/dL), and the cell viability was detected using cell counting kit-8 (CCK-8). HG-treated MC3T3-E1 cells were transfected with siALK7 or ALK7 overexpression plasmid or siNrf2, and then the viability and apoptosis were detected by CCK-8 and flow cytometry. The levels of reactive oxygen species (ROS), collagen I and calcification nodule were determined by oxidative stress kits, Enzyme-linked immunosorbent assay and Alizarin red staining. The expressions of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and osteoblast-associated genes were determined by quantitative real-time PCR (qRT-PCR) and Western blot. Results: Cell viability was reduced with HG treatment. Silencing ALK7 inhibited the effect of HG on increasing cell apoptosis and ROS production, reduced cell viability, mineralized nodules, and downregulated collagen I and osteoblast-associated genes expression in MC3T3-E1 cells. ALK7 silencing activated the Nrf2/HO-1 signaling pathway by affecting expressions of HO-1 and Nrf2. ALK7 overexpression had the opposite effects. In addition, siNrf2 partially reversed the effects of ALK7 silencing on HG-induced MC3T3-E1 cells. Conclusion: ALK7 silencing protected osteoblasts under HG condition possibly through activating the Nrf2/HO-1 pathway.

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Defense and protection mechanisms in lung exposed to asbestiform fiber: the role of macrophage migration inhibitory factor and heme oxygenase-1

European Journal of Histochemistry ◽

10.4081/ejh.2020.3073 ◽

2020 ◽

Vol 64 (2) ◽

Author(s):

Carla Loreto ◽

Rosario Caltabiano ◽

Adriana Carol Eleonora Graziano ◽

Sergio Castorina ◽

Claudia Lombardo ◽

...

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Lung Fibroblasts ◽

Heme Oxygenase 1 ◽

Macrophage Migration

Fluoro-edenite (FE), an asbestiform fiber, is responsible for many respiratory pathologies: chronic obstructive diseases, pleural plaques, fibrosis, and malignant mesothelioma. Macrophage migration inhibitory factor (MIF) is one of the first cytokines produced in response to lung tissue damage. Heme oxygenase-1 (HO-1) is a protein with protective effects against oxidative stress. It is up regulated by several stimuli including pro-inflammatory cytokines and factors that promote oxidative stress. In this research, the in vivo model of sheep lungs naturally exposed to FE was studied in order to shed light on the pathophysiological events sustaining exposure to fibers, by determining immunohistochemical lung expression of MIF and HO-1. Protein levels expression of HO-1 and MIF were also evaluated in human primary lung fibroblasts after exposure to FE fibers in vitro. In exposed sheep lungs, MIF and HO-1 immunoexpression were spread involving the intraparenchymal stroma around bronchioles, interstitium between alveoli, alveolar epithelium and macrophages. High MIF immunoexpression prevails in macrophages. Similar results were obtained in vitro, but significantly higher values were only detected for HO-1 at concentrations of 50 and 100 μg/mL of FE fibers. MIF and HO-1 expressions seem to play a role in lung self-protection against uncontrolled chronic inflammation, thus counteracting the strong link with cancer development, induced by exposure to FE. Further studies will be conducted in order to add more information about the role of MIF and HO-1 in the toxicity FE-induced.

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Puerarin protects against high glucose-induced acute vascular dysfunction: Role of heme oxygenase-1 in rat thoracic aorta

Vascular Pharmacology ◽

10.1016/j.vph.2008.11.003 ◽

2009 ◽

Vol 50 (3-4) ◽

pp. 110-115 ◽

Cited By ~ 33

Author(s):

Xiang-hong Meng ◽

Chao Ni ◽

Li Zhu ◽

Yue-liang Shen ◽

Lin-lin Wang ◽

...

Keyword(s):

Thoracic Aorta ◽

Heme Oxygenase ◽

High Glucose ◽

Vascular Dysfunction ◽

Heme Oxygenase 1 ◽

Rat Thoracic Aorta

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Heme oxygenase expression and Nrf2 signaling during hibernation in ground squirrelsThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y10-017 ◽

2010 ◽

Vol 88 (3) ◽

pp. 379-387 ◽

Cited By ~ 26

Author(s):

Zhouli Ni ◽

Kenneth B. Storey

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Nuclear Translocation ◽

Muscle Power ◽

Ground Squirrels ◽

Heme Oxygenase 1 ◽

Antioxidant Defences ◽

Protein Levels ◽

Brown Adipose ◽

Distribution Studies

Mammalian hibernation is composed of long periods of deep torpor interspersed with brief periods of arousal in which the animals, fueled by high rates of oxygen-based thermogenesis in brown adipose tissue and skeletal muscle, power themselves back to euthermic (~37 °C) body temperatures. Strong antioxidant defences are important both for long-term cytoprotection during torpor and for coping with high rates of reactive oxygen species generated during arousal. The present study shows that the antioxidant enzyme heme oxygenase 1 (HO1) is strongly upregulated in selected organs of thirteen-lined ground squirrels (Spermophilus tridecemlineatus) during hibernation. Compared with euthermic controls, HO1 mRNA transcript levels were 1.4- to 3.8-fold higher in 5 organs of hibernating squirrels, whereas levels of the constitutive isozyme HO2 were unchanged. Similarly, HO1 protein levels increased by 1.5- to 2.0-fold in liver, kidney, heart, and brain during torpor. Strong increases in the levels of the Nrf2 transcription factor and its heterodimeric partner protein, MafG, in several tissues indicated the mechanism of activation of hibernation-responsive HO1 gene expression. Furthermore, subcellular distribution studies with liver showed increased nuclear translocation of both Nrf2 and MafG in torpid animals. The data are consistent with the suggestion that Nrf2-mediated upregulation of HO1 expression provides enhanced antioxidant defence to counter oxidative stress in hibernating squirrels during torpor and (or) arousal.

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P6283Downregulation of Tim44 exacerbates oxidative stress-induced ROS production and cardiomyocytes death by reducing mitochondrial SOD2

European Heart Journal ◽

10.1093/eurheartj/ehz746.0881 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Ikeda ◽

S Matsushima ◽

K Okabe ◽

A Ishikita ◽

T Tadokoro ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Remodeling ◽

Protein Import ◽

Mitochondrial Fraction ◽

Left Ventricular ◽

Protein Carbonylation ◽

Neonatal Rat ◽

Ros Production ◽

Protein Levels

Abstract Background Mitochondrial dysfunction has been highlighted as a critical driver of cardiac remodeling and failure. Mitochondria contains about 1500 proteins, 99% of which are encoded in the nuclear genome. Therefore, protein import into mitochondria is essential to maintain mitochondrial function. Previous reports suggest that nuclear-encoded mitochondrial precursor proteins import into mitochondria by multiple complex; translocase of outer membrane (TOM), translocase of inner membrane (TIM), and protein associated motor (PAM). However, the role of these protein import machineries of mitochondria in cardiac remodeling remains to be elucidated. Objective The purpose of this study was to elucidate the role of TOM, TIM, and PAM complex in cardiac remodeling and cardiomyocyte death. Methods and results C57BL/6J mice were subjected to myocardial infarction (MI) by permanent ligation of left anterior descending artery. Four weeks after operation, MI-mice demonstrated left ventricular (LV) dilation (LV end-diastolic dimension: 3.91 vs. 5.54 mm, n=8–11, p<0.05) and dysfunction (LV fractional shortening: 33.3 vs. 7.7%, n=8–11, p<0.05). Tim44 protein levels, a component of PAM complex, in mitochondrial fraction from non-infarcted left ventricle were significantly decreased compared with those in the heart from sham-operated mice by 39% (p<0.05), whereas other proteins related to TOM, TIM and PAM complex such as Tom20, Tom22, Tom40, Tom70, Tim22, Tim23 and mtHSP70 were not altered between MI-mice and sham-mice. In addition, blue-native polyacrylamide gel electrophoresis revealed that a protein complex associated to Tim44 was significantly decreased in non-infarcted LV by 40% (p<0.05). Superoxide dismutase 2 (SOD2), a mitochondrial matrix protein, was decreased in mitochondrial fraction from non-infarcted LV by 20% (p<0.05), accompanied by enhancing protein carbonylation, a marker of oxidative stress, by 40% (p<0.05). To assess the role of Tim44, it was downregulated by small interfering RNA in cultured neonatal rat ventricular myocytes (NRVMs). Knockdown of Tim44 significantly decreased SOD2 protein levels in mitochondrial fractionation (22%, p<0.05), with no significant changes in its mRNA levels. Furthermore, knockdown of Tim44 significantly increased protein carbonylation (20%, p<0.05) and cleaved caspase 3 (47%, p<0.05) and decreased cell viability (69%, p<0.05), assessed by cell titer assay, in H2O2-treatred NRVMs. Conclusions Downregulation of Tim44 exacerbates oxidative stress-induced ROS production and cardiomyocytes death, which is associated with a decrease in mitochondrial SOD2. Endogenous Tim44 might play a protective role in cardiac remodeling by attenuating oxidative stress and cardiomyocyte death via SOD2 import into mitochondria.

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Novel Insights into the Vasoprotective Role of Heme Oxygenase-1

International Journal of Hypertension ◽

10.1155/2012/127910 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 18

Author(s):

Emanuela Marcantoni ◽

Luigia Di Francesco ◽

Melania Dovizio ◽

Annalisa Bruno ◽

Paola Patrignani

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Vascular Wall ◽

Heme Oxygenase 1 ◽

Antiinflammatory Effect ◽

Atherosclerotic Lesions ◽

Inflammatory Processes ◽

Cox 2 ◽

Endogenous Antioxidant

Cardiovascular risk factors contribute to enhanced oxidative stress which leads to endothelial dysfunction. These events trigger platelet activation and their interaction with leukocytes and endothelial cells, thus contributing to the induction of chronic inflammatory processes at the vascular wall and to the development of atherosclerotic lesions and atherothrombosis. In this scenario, endogenous antioxidant pathways are induced to restrain the development of vascular disease. In the present paper, we will discuss the role of heme oxygenase (HO)-1 which is an enzyme of the heme catabolism and cleaves heme to form biliverdin and carbon monoxide (CO). Biliverdin is reduced enzymatically to the potent antioxidant bilirubin. Recent evidence supports the involvement of HO-1 in the antioxidant and antiinflammatory effect of cyclooxygenase(COX)-2-dependent prostacyclin in the vasculature. Moreover, the role of HO-1 in estrogen vasoprotection is emerging. Finally, possible strategies to develop novel therapeutics against cardiovascular disease by targeting the induction of HO-1 will be discussed.

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Deletion ofHerpud1Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2016/6163934 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Thuong Manh Le ◽

Koji Hashida ◽

Hieu Minh Ta ◽

Mika Takarada-Iemata ◽

Koichi Kokame ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Heme Oxygenase ◽

Active Form ◽

Heme Oxygenase 1 ◽

Protein Levels ◽

The Status ◽

Mptp Administration

Herp is an endoplasmic reticulum- (ER-) resident membrane protein that plays a role in ER-associated degradation. We studied the expression of Herp and its effect on neurodegeneration in a mouse model of Parkinson’s disease (PD), in which both the oxidative stress and the ER stress are evoked. Eight hours after administering a PD-related neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to mice, the expression of Herp increased at both the mRNA and the protein levels. Experiments usingHerpud1+/+andHerpud1−/−mice revealed that the status of acute degeneration of nigrostriatal neurons and reactive astrogliosis was comparable between two genotypes after MPTP injection. However, the expression of a potent antioxidant, heme oxygenase-1 (HO-1), was detected to a higher degree in the astrocytes ofHerpud1−/−mice than in the astrocytes ofHerpud1+/+mice 24 h after MPTP administration. Further experiments using cultured astrocytes revealed that the stress response against MPP+, an active form of MPTP, and hydrogen peroxide, both of which cause oxidative stress, was comparable between the two genotypes. These results suggest that deletion ofHerpud1may cause a slightly higher level of initial damage in the nigrastrial neurons after MPTP administration but is compensated for by higher induction of antioxidants such as HO-1 in astrocytes.

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