Expression of heme oxygenase-1 in the lung in chronic hypoxia

Abstract

Heme oxygenase (HO)-1 is an oxygen-dependent enzyme that may regulate vascular tone and cell proliferation through the production of carbon monoxide (CO). We tested the hypothesis that HO-1 is upregulated in the lung in chronic hypoxia by exposing male Sprague-Dawley rats to 17,000 feet (395 Torr) for 0, 1, 3, 7, 14, or 21 days. After exposure, blood gases, carboxyhemoglobin (COHb) levels, and hematocrit were measured, and the lungs were either inflation fixed for immunohistochemistry or frozen for later measurement of HO enzyme activity, Western blot for HO-1 protein, and RT-PCR for HO-1 mRNA. The heart was excised and weighed, and the right-to-left heart weight ratio was determined. During hypoxia, the hematocrit increased progressively, reaching significantly higher values than the control value after 3 days. COHb levels increased above the control value after 1 day of hypoxia and increased progressively between 14 and 21 days, whereas arterial PO(2) and arterial PCO(2) did not vary significantly. HO-1 protein determined by Western blot increased for the first 7 days and declined thereafter; however, enzyme activity was elevated only after 1 day. Changes in HO-1 during hypoxia were localized by immunohistochemistry to inflammatory cells (early) and newly muscularized arterioles (later). Lung HO-1 mRNA normalized to glyceraldehyde-3-phosphate dehydrogenase was increased after 1 and 21 days. The data indicate that lung HO-1 protein and activity are upregulated only during early chronic hypoxia, whereas persistent COHb elevations indicate high endogenous CO production rates at nonpulmonary sites. If CO has antiproliferative properties, the lack of HO enzyme activity in the lung may be permissive for pulmonary vascular proliferation in hypoxia.

Hypoxia Inducible Factor-1 Alpha Correlates the Expression of Heme Oxygenase 1 Gene in Pulmonary Arteries of Rat with Hypoxia-induced Pulmonary Hypertension

“…However, in the lung, the HO-1 increase preceded the onset of erythrocytosis, and this response was not maintained as the hemoglobin concentration increased. This observation provides further indirect evidence that HO-1 induction in the lung is a specific response to hypoxia [2]. HO-1 enzyme activity in the lung increases in accordance with the immunoreactive protein after 7 d of hypoxia; however, it is similar to the control value after 14 and 21 d of hypoxia also the immunoreactive protein increased persistently.…”

“…Hypoxia induces the expression of HIF-1α, which then activates the transcriptions of some hypoxia-responsive genes. Expression of HO-1 protein is up-regulated in the pulmonary arteries of chronically hypoxic rats [2]. Recent studies have demonstrated that HIF-1α is essential for the hypoxic regulation of the HO-1 gene transcription in pulmonary arterial endothelial cells and pulmonary arterial smooth muscle cells in vitro [3].…”

The cellular stress response of the scleractinian coral Goniopora columna during the progression of the black band disease

“…On the contrary, during the night, biogeochemical conditions at the base of the mat are typically hypoxic or anoxic with high levels of sulfide and low pH (reviewed in Sato et al 2016). It is well known that usually both hyperoxia and hypoxia, as well as the exposition to sulfide, may lead to the upregulation of the antioxidant systems HO-1 and MnSOD as well as that of Hsps (Lee et al 1997;Yamashita et al 1997;Carraway et al 2000;Garrido et al 2001;Richier et al 2003;Calvert et al 2009;Mohindra et al 2015). Moreover, sulfide is toxic to most eukaryotes, inhibiting electron transport in aerobic respiration, leading to apoptosis and tissue necrosis, and increasing the cellular oxidative stress (Vismann 1991).…”

The Anti-inflammatory Mechanism of Heme Oxygenase-1 Induced by Hemin in Primary Rat Alveolar Macrophages

“…HO-1 and its byproducts have antiinflammatory, antiapoptotic, and antiproliferative effects [13,14]. HO-1 is highly expressed in airways induced by oxidative stress, including hyperoxia, hypoxia, endotoxemia, heavy metal exposure, bleomycin, diesel exhaust particles, and allergen exposure [15][16][17][18]. HO-1 plays an important role in preventing airway inflammation.…”