International Journal of Molecular Zoology, 2025, Vol.15, No.2, 48-57 http://animalscipublisher.com/index.php/ijmz 50 red blood cells under hypoxia, reflecting the convergent evolutionary characteristics of different groups to hypoxic environments (van der Weele and Jeffery, 2022). However, some studies have pointed out that the cardiovascular response patterns of different fish species vary greatly. Hypoxia-tolerant fish such as catfish may be more inclined to maintain a stable cardiac output to ensure tissue oxygen supply (Mandic and Regan, 2018). In addition to hemodynamic regulation, catfish also increase the oxygen-carrying capacity of blood at the molecular level by activating pathways such as erythropoietin (EPO). For example, studies on zebrafish have shown that upregulation of the HIF pathway can promote erythropoiesis and enhance hypoxia tolerance. It is speculated that a similar mechanism also exists in catfish: hypoxia-induced HIF-1α stabilization will promote the expression of genes such as EPO, thereby stimulating erythropoiesis (Cai et al., 2020). In addition, the hypoxic environment will also prompt the catfish body to increase the density of tissue capillaries to shorten the oxygen diffusion distance. Figure 1 Metabolic regulatory mechanisms of fish hypoxia tolerance (Adopted from Ma et al., 2023) Image caption: Fish species with low hypoxia tolerance (left) mainly rely on fatty acid β-oxidation for energy supply; fish species with high hypoxia tolerance (right) inhibit Atgl, Pparα, and Cpt1b to reduce fatty acid metabolism (Adopted from Ma et al., 2023) 3 The Basis of Hhypoxia Tolerance at the Genomic Level of Catfish 3.1 Structure and regulation of core genes of the HIF pathway The core genes of the HIF pathway play a central role in catfish's adaptation to hypoxia: they achieve transcriptional regulation of many downstream effector genes (such as hemoglobin, EPO, glycolytic enzymes, VEGF, etc.) through oxygen-dependent stability regulation. The optimization of the function and structure of HIF pathway genes in catfish during evolution helps them to quickly activate cell protection mechanisms in repeated hypoxic habitats, thereby improving hypoxia survival (Chen et al., 2020; Babin et al., 2024). Babin et al. (2024) compared the HIFα and PHD sequences of various fish and found that in fish with high hypoxia tolerance, unique mutations were fixed at certain amino acid sites of the HIF-2α protein, which changed the physicochemical properties of the protein. These variations were significantly correlated with the lower critical oxygen partial pressure (P_crit) of these fish. In addition, the HIF-3α subunit unique to aquatic animals such as catfish is also worthy of attention. A study found that knocking out the zebrafish hif-3α gene resulted in delayed red blood cell development and reduced hypoxia tolerance, indicating that HIF-3α also plays an important role in hypoxic hematopoiesis and tolerance (Cai et al., 2020).
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