Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2

Adachi, Tomohiko; Ishikawa, Kazunobu; Hida, Wataru; Matsumoto, Hayato; Matsumoto, Takayuki; Date, Fumiko; Ogawa, Kōichi; Takeda, Kazuhisa; Furuyama, Kazumichi; Zhang, Yongzhao; Kitamuro, Tomomi; Ogawa, Hiroyasu; Maruyama, Yukio; Shibahara, Shigeki

doi:10.1016/j.bbrc.2004.05.195

Cited by 74 publications

(67 citation statements)

References 40 publications

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“…A potential role of HO-2 in oxygen-sensing mechanisms (Adachi et al 2004) and in protection against diabetes and obesity has emerged from studies using the HO-2 knockout mouse model (reviewed in Satarug and Moore 2012). HO-1 and HO-2 both are localized to the endoplasmic reticulum (ER).…”

Section: Modulation Of Cadmium Toxicity By a Stress Response Mechanismmentioning

confidence: 99%

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

Satarug

Vesey

Gobé

2017

Tohoku J. Exp. Med.

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Section: Modulation Of Cadmium Toxicity By a Stress Response Mechanismmentioning

confidence: 99%

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

Satarug

Vesey

Gobé

2017

Tohoku J. Exp. Med.

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“…In addition to iron recycling, there is evidence for participation of HO-2 in an oxygen-sensing mechanism (Adachi et al 2004;Shibahara et al 2007). Intriguingly, a large body of circumstantial evidence, including human genetic variant association (Shibahara 2003;Bao et al 2010), suggests a potential role for these enzymes of heme catabolism in the protection against the development of a range of chronic diseases, including type-2 diabetes, obesity and oxidative damage, resulting from hyperglycemic conditions, known as glucose toxicity (Goodman et al 2006;Ndisang et al 2009;Sodhi et al 2009;Hosick and Stec 2011).…”

Section: Heme Oxygenase-1 and Heme Oxygenase-2mentioning

confidence: 99%

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

Satarug

2012

Tohoku J. Exp. Med.

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Many decades after an outbreak of severe cadmium poisoning, known as Itai-itai disease, cadmium continues to pose a significant threat to human health worldwide. This review provides an update on the effects of this environmental toxicant cadmium, observed in numerous populations despite modest exposure levels. In addition, it describes the current knowledge on the link between heme catabolism and glycolysis. It examines novel functions of heme oxygenase-2 (HO-2) that protect against type 2-diabetes and obesity, which have emerged from diabetic/obese phenotypes of the HO-2 knockout mouse model. Increased cancer susceptibility in type-2 diabetes has been noted in several large cohorts. This is a cause for concern, given the high prevalence of type-2 diabetes worldwide. A lifetime exposure to cadmium is associated with pre-diabetes, diabetes, and overall cancer mortality with sex-related differences in specific types of cancer. Liver and kidney are target organs for the toxic effects of cadmium. These two organs are central to the maintenance of blood glucose levels. Further, inhibition of gluconeogenesis is a known effect of heme, while cadmium has the propensity to alter heme catabolism. This raises the possibility that cadmium may mimic certain HO-2 deficiency conditions, resulting in diabetic symptoms. Intriguingly, evidence has emerged from a recent study to suggest the potential interaction and co-regulation of HO-2 with the key regulator of glycolysis: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4). HO-2 could thus be critical to a metabolic switch to cancer-prone cells because the enzyme PFKFB and glycolysis are metabolic requirements for cell proliferation and resistance to apoptosis.

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“…The targeted fraction concentration of O 2 or CO 2 was obtained within 20 sec, and maintained for 3 min. The ventilatory responses to hypoxia were measured for 15 ~ 20 sec at the peak response during 3 min and those to hypercapnia were measured for the last 15 ~ 20 sec during 3 min (Mizusawa et al 1994;Ogawa et al 1995;Tabata et al 2001;Adachi et al 2004), with an interval of at least 30 min and in random order.…”

Section: Acute Hypoxic and Hypercapnic Ventilatory Responsesmentioning

confidence: 99%

“…The response of each respiratory variable was assessed as the value during hypoxia or hypercapnia minus the corresponding basal value during room air breathing (Mizusawa et al 1994;Adachi et al 2004). …”

Section: Acute Hypoxic and Hypercapnic Ventilatory Responsesmentioning

confidence: 99%

Mice with Blunted Hypoxic Ventilatory Response are Susceptible to Respiratory Disturbance during Hypoxia

Adachi

Ogawa

Okabe

et al. 2006

Tohoku J. Exp. Med.

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Hypoxia causes a life-threatening situation, and the ventilatory response to hypoxia plays an important role in preventing death. We have hypothesized that persons with a blunted hypoxic ventilatory response may have a weak defense response to hypoxic episodes and be susceptible to fatal respiratory disturbances. However, precise correlations between the hypoxic ventilatory response and respiratory disturbances are not well understood. In the present study we examined the hypoxic and hypercapnic ventilatory responses in nine inbred mouse strains (A/J, AKR/N, BALB/c, C3H/He, C57BL/6, DBA/2, NZW, SWR/J, and 129Sv). Breathing frequency, tidal volume and minute ventilation of unanesthetized and unrestrained mice were assessed by whole body plethysmography. Age-matched mice were exposed for 3 min to 10% O 2 in N 2 gas or 10% CO 2 in hyperoxic gas to determine the acute ventilatory response to chemical stimuli. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the highest in AKR/N mice and the lowest in SWR/J mice. These findings suggest that genetic factors may have influenced the hypoxic ventilatory response but not the hypercapnic ventilatory response. To examine the effects of severe hypoxic stress on the respiratory cycle, we exposed the strain with the highest or lowest hypoxic ventilatory response to 6% O 2 in N 2 until the onset of apnea. The "appearance time of apnea", which is defined as the time from the hypoxic loading to the onset of apnea, was shorter in the SWR/J strain than in the AKR/N strain. We suggest that a lower hypoxic ventilatory response may be a risk factor for apnea under hypoxia.

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Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2

Cited by 74 publications

References 40 publications

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

Mice with Blunted Hypoxic Ventilatory Response are Susceptible to Respiratory Disturbance during Hypoxia

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