Hmox2, short for heme oxygenase-2, is one of the two isozymes of the heme oxygenase enzyme system. It catalyzes the degradation of heme into carbon monoxide (CO), ferrous iron, and biliverdin, which is then converted to bilirubin. These products are involved in modulating key cellular processes such as inflammation, cell proliferation, apoptosis, and antioxidant defense [1,6]. Hmox2 is a constitutive form, distinct from the inducible Hmox1, and is encoded by its own gene. The heme oxygenase system and Hmox2 play an important role in maintaining normal cell function and are involved in multiple biological pathways [1,6].

In Tibetans, the Hmox2 gene harbors potentially adaptive variants. Association analyses in Tibetan populations showed a male-specific association between Hmox2 variants and hemoglobin levels. The derived C allele at rs4786504:T>C could increase Hmox2 expression, potentially leading to more efficient heme breakdown and helping maintain a relatively low hemoglobin level at high altitude, suggesting its role in high-altitude adaptation [2]. In European sea-level residents, a functional single nucleotide polymorphism of Hmox2 (rs4786504 T>C) is involved in individual chemosensitivity to acute hypoxia. Carriers of the ancestral T allele have significantly lower resting and exercise hypoxic ventilatory responses than C/C homozygous carriers, and the T allele carriers have a higher risk of severe high-altitude illness (SHAI) [3]. Genome-wide association studies also identified a risk variant in Hmox2 specific for migraine with aura, indicating its potential role in migraine pathophysiology [4]. Additionally, Hmox2 has been identified as a novel biomarker for lung tumor-initiating cells (TIC), and a small molecule probe targeting Hmox2 can inhibit tumor growth in a cancer mouse model [5].

In conclusion, Hmox2 plays essential roles in multiple biological processes. Through genetic studies in different populations and in vivo models, it has been shown to be involved in high-altitude adaptation, response to acute hypoxia, migraine, and lung cancer. These findings highlight the importance of Hmox2 in understanding the mechanisms of these specific disease conditions and biological adaptations.

References:

1. Ryter, Stefan W. 2022. Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders. In Antioxidants (Basel, Switzerland), 11, . doi:10.3390/antiox11030555. https://pubmed.ncbi.nlm.nih.gov/35326205/

2. Yang, Deying, Peng, Yi, Cui, Chaoying, Qi, Xuebin, Su, Bing. 2015. HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans. In Human mutation, 37, 216-23. doi:10.1002/humu.22935. https://pubmed.ncbi.nlm.nih.gov/26781569/

3. Fabries, Pierre, Drogou, Catherine, Sauvet, Fabien, Gomez-Merino, Danielle, Chennaoui, Mounir. 2022. The HMOX2 polymorphism contributes to the carotid body chemoreflex in European sea-level residents by regulating hypoxic ventilatory responses. In Frontiers in medicine, 9, 1000786. doi:10.3389/fmed.2022.1000786. https://pubmed.ncbi.nlm.nih.gov/36405624/

4. Hautakangas, Heidi, Winsvold, Bendik S, Ruotsalainen, Sanni E, Palotie, Aarno, Pirinen, Matti. 2022. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. In Nature genetics, 54, 152-160. doi:10.1038/s41588-021-00990-0. https://pubmed.ncbi.nlm.nih.gov/35115687/

5. Kim, Jong-Jin, Lee, Yong-An, Su, Dongdong, Kang, Nam-Young, Chang, Young-Tae. 2019. A Near-Infrared Probe Tracks and Treats Lung Tumor Initiating Cells by Targeting HMOX2. In Journal of the American Chemical Society, 141, 14673-14686. doi:10.1021/jacs.9b06068. https://pubmed.ncbi.nlm.nih.gov/31436967/

6. Ayer, Anita, Zarjou, Abolfazl, Agarwal, Anupam, Stocker, Roland. . Heme Oxygenases in Cardiovascular Health and Disease. In Physiological reviews, 96, 1449-508. doi:10.1152/physrev.00003.2016. https://pubmed.ncbi.nlm.nih.gov/27604527/