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  • MRcKO mice showed a comparable

    2021-10-19

    MRcKO mice showed a comparable degree of cardiac remodeling compared to control (MRf/f) mice. Moreover, the worse cardiac remodeling in pressure-overloaded GRcKO mice is not due to compensatory activation of cardiomyocyte MR, because GRMRdcKO mice displayed cardiac remodeling to the same extent as GRcKO mice in response to pressure overload. Clinically, MR antagonist improves the prognosis of patients with post-myocardial infarction and heart failure when administered in addition to renin-angiotensin system inhibitor and β-blocker [24] [25]. Our experimental results suggest that, at least in mice, the role of cardiomyocyte MR in cardiac remodeling under pressure overload is less important compared with cardiomyocyte GR. Clinically, MR antagonist may improve the prognosis of patients with LV dysfunction by suppressing MR in ZCL278 other than cardiomyocytes. It was shown that glucocorticoids have a protective effect against muscle dystrophy models [26], as well as against excessive hypertrophic response after induction of pressure overload by TAC. Although further studies are clearly needed, we might speculate that both of those therapeutic effects are due to glucocorticoid-induced KLF15. Indeed, KLF15 is shown to have a pleiotropic function in muscle including metabolism. We, however, cannot exclude the possibility that other GR target genes may play a role in those effects. The review of available clinical studies demonstrated no harm and a possible mortality benefit of corticosteroids in acute myocardial infarction [27]. However, for clinical practice, corticosteroids are never used for treatment after acute myocardial infarction because of concern regarding the potential for impaired wound healing and the resulting myocardial rupture. Regarding myocarditis, the benefit of corticosteroids in the acute phase has not been determined. In cases where inflammation is prolonged and hemodynamic improvements are not obtained, corticosteroids are used in clinical practice and are sometimes remarkably effective. However, there is a claim that intervention with corticosteroids should be judged depending on the mechanism of the development of myocarditis, either virus persistent infection or autoimmune mechanism [28]. All these arguments were based on the immunosuppressive effect of corticosteroids. From now on, we should consider pros and cons of treatment intervention by considering the direct action of corticosteroids on cardiomyocytes in addition to immune cells. In conclusion, GR works as a repressor of pathological cardiac hypertrophy in response to pressure overload. The caveat is that GR-mediated transcription is suppressed under pressure overload. Much effort is still required to develop an optimal therapeutic strategy to target cardiac GR or increase KLF15 function in order to protect against maladaptive cardiac remodeling under pressure overload. The following are the supplementary data related to this article.
    Sources of funding This study was supported by a Japan Society for the Promotion of Science KAKENHI grant 22659158 (2010−2011), a Takeda Science Foundation Research Grant (2011), Keio Gijuku Academic Development Funds (2011), and a grant from The Vehicle Racing Commemorative Foundation (2012–2014) (to Dr. Sano).
    Disclosures
    Acknowledgements The authors are grateful to Yoshiko Miyake (Keio University, Japan) for technical assistance. This study was supported (partly) by the Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo.
    Introduction The corticosteroid receptors (CR), which include the glucocorticoid (GR) and mineralocorticoid receptors (MR), belong to the nuclear receptor family of proteins. The genes that encode for these proteins evolved from a common ancestor steroid receptor (SR) present in the chordates, following rounds of whole genome or gene duplication events, with the CRs emerging in the vertebrate lineage approximately 500MYA. A further whole genome duplication event in the teleost lineage between 320 and 350MYA has given rise to 2 GR isoforms (Fig. 1). The majority of functional and structural analysis has been carried out on the tetrapod GRs and these studies have been used to compare and contrast the properties of the basal actinopterygian (ray-finned fish) GRs and the teleost GRs (Arterbery et al., 2011, Becker et al., 2008, Bury et al., 2003, Ducouret et al., 1995, Greenwood et al., 2003, Kim et al., 2011, Li et al., 2012, Miyagawa et al., 2015, Oka et al., 2015, Stolte et al., 2008, Sturm et al., 2005, Sturm et al., 2010, Sturm et al., 2011). This short review will first describe the structure and function of the human GRs, and then briefly describe the evolution of the steroid receptors, that gave rise to the actinopterygian GRs. Finally, the structure and function of the two teleost GRs will be discussed and potential reasons for their retention proposed.