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  • We addressed the role of GSNOR mediated T cell activation

    2022-05-27

    We addressed the role of GSNOR-mediated T-cell activation in HHcy-accelerated atherosclerosis in vivo by two mouse models. Generated for the first time, GSNOR-/-ApoE-/- double knock-out mice showed decreased atherosclerosis in aortic roots in response to HHcy. The specificity of GSNOR ablation in T Fmoc-Trp-OH contributing to the decreased atherosclerosis was further verified by the T-cell adoptive transfer experiments. In addition to T cells, other cell types may participate in the amelioration of atherosclerosis in GSNOR-/-ApoE-/- mice. The role of HHcy-initiated endothelial cell dysfunction and inflammatory monocyte generation and differentiation during atherogenesis was well established by Wang et al. [40], [41], [42] Ablation of GSNOR in these cell types may imbalance the protein S-nitrosylation levels and commit to the development of atherosclerosis. As evidenced by recent studies from Liu et al., [8], [9] HHcy reduces the level of protein S-nitrosylation in vascular endothelial cells during HHcy-induced atherosclerosis, and supplementation with the NO donor NONOate could reverse the atherosclerosis. The relevance of GSNOR in HHcy-induced cardiovascular disease was demonstrated by the findings in human CAD patients with HHcy. The level of plasma Hcy was positively correlated with PBMC Gsnor expression and IFN-γ-producing T cells but inversely with S-nitrosylation level in T cells, which indicates a proinflammatory role of GSNOR in human T cells. These findings were consistent with the elevated GSNOR level found in human asthmatic lungs and reduced lung inflammatory responses induced by the GSNOR inhibitor SPL-334 [43]. The signaling pathway downstream of GSNOR in human T cells from CAD patients should include activation of Akt, which remains to be verified. These translational studies suggest that GSNOR can be an indicator of vascular disease.
    Acknowledgments We thank Dr. Limin Liu (University of California, San Francisco) for providing the GSNOR-/- mice, Prof. John Y.-J. Shyy (University of California, San Diego) for revising the manuscript, and Prof. Chu Wang and Dr. Nan Chen (Peking University) for Akt structural analysis. The Figure was partly generated by using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (available at http://smart.servier.com).
    Introduction Male hypogonadism is defined as a combination of low serum testosterone level and associated symptoms, such decreased energy, low libido, weight gain, and loss of muscle mass. The diagnosis of male hypogonadism affects up to 24% of men older than 40 years. Hypogonadism is divided into 3 distinct classifications: primary (testicular failure), secondary (hypothalamic-pituitary failure), and compensated (eugonadism with compensatory increased pituitary hormone secretion). Secondary hypogonadism, the most common form with an estimated prevalence of 11.8%, results from decreased pituitary secretion of luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) or deficiencies in gonadotropin-releasing hormone (GnRH) production from the hypothalamus. Most etiologies of secondary hypogonadism remain idiopathic and associated with comorbid conditions such as excess opioid use, arthritis, diabetes, and obesity.4, 5 Despite the high prevalence and association with common comorbidities, few studies have identified an etiology for secondary hypogonadism. The current standard of care for hypogonadism, regardless of the cause, is testosterone replacement therapy. Unfortunately, testosterone replacement has side effects such as infertility, polycythemia, gynecomastia, hypertension, and possibly atherosclerosis. This treatment is undesirable for many men, especially those who are concerned about fertility. Identifying mechanisms of secondary hypogonadism could enable recognition of strategies to increase testosterone without administering exogenous testosterone therapy. Reactive nitrogen species (RNS) are similar to free oxygen radicals called reactive oxygen species (ROS). Like ROS, RNS regulate normal cellular function at physiologic levels, but in excessive amounts can cause nitrosative stress and affect semen parameters and reproductive hormone signaling.7, 8 Emerging Fmoc-Trp-OH data suggest that the nitroso-redox balance also can play a critical role in the regulation of LH signaling and therefore an imbalance can lead to secondary hypogonadism.9, 10