Cyp2c44 Gene Disruption Is Associated With Increased Hematopoietic Stem Cells: Implication in Chronic Hypoxia-induced Pulmonary Hypertension
We have recently demonstrated that disruption of the murine cytochrome P450 2c44 gene exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found that Cyp2c44 gene disruption also increases hematopoietic stem cell (HSC) number in bone marrow and blood. Therefore, the objective of this study was to investigate whether Cyp2c44 disruption regulates HSC phenotype and whether increases in differentiated HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries. Our findings demonstrated that lack of a CYP2C44 epoxygenase, which produces epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids, increases: 1] HSC (CD34+, CD117+, and CD133+) numbers, 2] proangiogenic (CD34+, CD133+, CD34+, CD117+, CD133+) cells, and 3] immunogenic/inflammatory (CD34+, CD11b+, CD133+, CD11b+, F4/80+, CD11b+, and F4/80+ CD11b+) monocytes and macrophages, in bone morrow and blood as compared to wild type mice. Furthermore, we identified increased CD133+ and von Willebrand factor positive cells, which are derived from proangiogenic stem cells, in remodeled and occluded pulmonary arteries of CYP2C44-deficient mice exposed to chronic hypoxia. In conclusion, our results demonstrated that CYP2C44-derived lipid mediators played a critical role in regulating HSCs phenotype, because disruption of Cyp2c44 gene increased differentiated HSCs that potentially contributed to chronic hypoxia-induced pulmonary artery remodeling and occlusion.
Hashimoto, R., Joshi, S., Jiang, H., Capdevila, J., McMurtry, I., Laniado-Schwartzman, M., & Gupte, S. (2017). Cyp2c44 Gene Disruption Is Associated With Increased Hematopoietic Stem Cells: Implication in Chronic Hypoxia-induced Pulmonary Hypertension. American Journal of Physiology.Heart and Circulatory Physiology, 313 (2), H293-H303. https://doi.org/10.1152/ajpheart.00785.2016