bims-ho1def 2023-07-23 papers

bims-ho1def

Biomed News

on HO-1 Deficiency

Issue of 2023–07–23
six papers selected by
Julien H. Park, Universitätsklinikum Münster

Altered Expression of Heme Oxygenase 2 in Heme Oxygenase 1-deficient Mouse Embryos.
Neuroprotective Effects of Activin A against Cerebral Ischemia/Reperfusion Injury in Mice by Enhancing Nrf2 Expression to Attenuate Neuronal Ferroptosis.
Baf155 regulates skeletal muscle metabolism via HIF-1a signaling.
5-Methoxytryptophan ameliorates endotoxin-induced acute lung injury in vivo and in vitro by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway.
Biliverdin as a disease-modifying agent: An integrated viewpoint.
Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?

J Histochem Cytochem. 2023 Jul 22. 221554231189310

Altered Expression of Heme Oxygenase 2 in Heme Oxygenase 1-deficient Mouse Embryos.

Meenakshi Rana, Divya Bajaj, Pooja Choubey, Sidhant Jain, Sharmila Basu-Modak.

  Heme oxygenases (Hmoxs) are enzymes that catalyze the first and rate-limiting step in the degradation of heme to carbon monoxide, iron, and biliverdin. The two main isozymes, namely Hmox1 and Hmox2, are encoded by two different genes. Mutation of the Hmox1 gene in mice is known to cause extensive prenatal lethality, and limited information is available about the expression of Hmox proteins in developing mouse embryos. In this study, immunohistochemistry was used to perform a detailed investigation comparing Hmox proteins in Hmox1 wild-type and knockout (KO) mouse embryos collected from wild-type and heterozygous timed-matings. Western analysis for Hmoxs was also done in the organs of late-gestation embryos. The results demonstrated cytoplasmic and nuclear localization of Hmoxs in all the organs examined in wild-type embryos. Interestingly, Hmox2 immunoreactive protein signals were significantly low in most of the organs of mid- and late-gestation Hmox1-KO embryos. Furthermore, relative levels of Hmox2 were revealed to be significantly lower in the lung and kidney of late-gestation Hmox1-KO embryos by western analysis, which complemented the immunohistochemistry findings in these two organs. The current study provides detailed immunoexpression patterns of Hmox proteins in wild-type and Hmox1-KO mouse embryos in mid- and late-gestation.

Keywords:  heme oxygenase; immunohistochemistry; knockout; mouse embryos; phenotype

DOI:  https://doi.org/10.1369/00221554231189310
ACS Chem Neurosci. 2023 Jul 20.

Neuroprotective Effects of Activin A against Cerebral Ischemia/Reperfusion Injury in Mice by Enhancing Nrf2 Expression to Attenuate Neuronal Ferroptosis.

Fengzhi Wang, Ming Ma, Jiahui Yang, Xiaohua Shi, Jiaoqi Wang, Zhongxin Xu.

  Activin A (Act A) is a member of the transforming growth factor-β (TGF-β) superfamily and can protect against ischemic cerebral injury. Ferroptosis, a newly discovered type of programmed cell death, contributes to the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). However, little is known on whether Act A can modulate neuronal ferroptosis to protect against CIRI in a mouse model of middle cerebral artery occlusion (MCAO) and an HT22 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The results indicated that Act A treatment relieved CIRI by improving neurological deficits and reducing the infarct volume in mice. MCAO stimulated iron accumulation and malondialdehyde formation and upregulated ACSL4 expression but downregulated GPX4 expression, a hallmark of ferroptosis in the brain of mice. Treatment with Act A significantly mitigated MCAO-triggered ferroptosis in the brain of mice. Furthermore, Act A treatment enhanced the MCAO-upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression in the brains of mice. Similar results were observed in HT22 cells following OGD/R and pretreatment with Act A. The neuronal protective effect of Act A in HT22 cells was attenuated by treatment with ML385, an Nrf2 inhibitor. To conclude, Act A attenuated CIRI by enhancing Nrf2 expression and inhibiting neuronal ferroptosis.

Keywords:  activin A (Act A); cerebral ischemia/reperfusion injury (CIRI); ferroptosis; nuclear factor erythroid-2-related factor 2 (Nrf2); oxygen-glucose deprivation/reoxygenation (OGD/R)

DOI:  https://doi.org/10.1021/acschemneuro.3c00374
PLoS Biol. 2023 Jul 21. 21(7): e3002192

Baf155 regulates skeletal muscle metabolism via HIF-1a signaling.

Jong-Seol Kang, Dongha Kim, Joonwoo Rhee, Ji-Yun Seo, Inkuk Park, Ji-Hoon Kim, Daewon Lee, WonUk Lee, Ye Lynne Kim, Kyusang Yoo, Sunghwan Bae, Jongkyeong Chung, Rho Hyun Seong, Young-Yun Kong.

During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling.

DOI: https://doi.org/10.1371/journal.pbio.3002192
Inflamm Res. 2023 Jul 17.

5-Methoxytryptophan ameliorates endotoxin-induced acute lung injury in vivo and in vitro by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway.

Yang Ma, Zhixue Wang, Xiaoyang Wu, Zijian Ma, Jia Shi, Simeng He, Shaona Li, Xiangyun Li, Xiangkun Li, Yan Li, Jianbo Yu.

   BACKGROUND AND AIM: Endotoxin-induced acute lung injury (ALI) is a complicated and fatal condition with no specific or efficient clinical treatments. 5-Methoxytryptophan (5-MTP), an endogenous metabolite of tryptophan, was revealed to block systemic inflammation. However, the specific mechanism by which 5-MTP affects ALI still needs to be clarified. The purpose of this study was to determine whether 5-MTP protected the lung by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway.
METHODS AND RESULTS: We used lipopolysaccharide (LPS)-stimulated C57BL/6 J mice and MH-S alveolar macrophages to create models of ALI, and 5-MTP (100 mg/kg) administration attenuated pathological lung damage in LPS-exposed mice, which was associated with decreased inflammatory cytokines and oxidative stress levels, upregulated protein expression of Nrf2 and HO-1, and suppressed Caspase-1 activation and NLRP3-mediated pyroptosis protein levels. Moreover, Nrf2-deficient mice or MH-S cells were treated with 5-MTP to further confirm the protective effect of the Nrf2/HO-1 pathway on lung damage. We found that Nrf2 deficiency partially eliminated the beneficial effect of 5-MTP on reducing oxidative stress levels and inflammatory responses and abrogating the inhibition of NLRP3-mediated pyroptosis induced by LPS.
CONCLUSION: These findings suggested that 5-MTP could effectively ameliorate ALI by inhibiting NLRP3-mediated pyroptosis via the Nrf2/HO-1 signaling pathway.

Keywords:  5-Methoxytryptophan; Acute lung injury; Endotoxin; NLRP3 inflammasome; Pyroptosis

DOI:  https://doi.org/10.1007/s00011-023-01769-1
Free Radic Biol Med. 2023 Jul 15. pii: S0891-5849(23)00544-0. [Epub ahead of print]

Biliverdin as a disease-modifying agent: An integrated viewpoint.

Cesare Mancuso.

  Biliverdin is one of the three by-products of heme oxygenase (HO) activity, the others being ferrous iron and carbon monoxide. Under physiological conditions, once formed in the cell, BV is reduced to bilirubin (BR) by the biliverdin reductase (BVR). However, if BVR is inhibited by either genetic variants, as occurs in the Inuit ethnicity, or dioxin intoxication, BV accumulates in cells giving rise to a clinical syndrome known as green jaundice. Preclinical studies have demonstrated that BV not only has a direct antioxidant effect by scavenging free radicals, but also targets many signal transduction pathways, such as BVR, soluble guanylyl cyclase, and the aryl hydrocarbon receptor. Through these direct and indirect mechanisms, BV has shown beneficial roles in ischemia/reperfusion-related diseases, inflammatory diseases, graft-versus-host disease, viral infections and cancer. Unfortunately, no clinical data are available to confirm these potential therapeutic effects and the kinetics of exogenous BV in humans is unknown. These limitations have so far excluded the possibility of transforming BV from a mere by-product of heme degradation into a disease-modifying agent. A closer collaboration between basic and clinical researchers would be advantageous to overcome these issues and promote translational research on BV in free radical-induced diseases.

Keywords:  Bilirubin; Carbon monoxide; Drug development; Green jaundice; Heme oxygenase; Translational research

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.07.015
J Clin Invest. 2023 07 17. pii: e171965. [Epub ahead of print]133(14):

Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?

Abhinav Diwan.

Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.

DOI: https://doi.org/10.1172/JCI171965