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Molecular adaptations to endurance exercise and skeletal muscle fibre plasticity
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
To test the hypothesis that calcineurin-NFAT signalling could promote cardiac hypertrophy, the group created two transgenic mouse strains where either calcineurin or NFAT were overexpressed only in cardiomyocytes. Both transgenic lines developed pathological cardiac hypertrophy and many mice suffered either serious cardiac problems or died prematurely (27). Treating the mice with the calcineurin inhibitor drug cyclosporine A completely reversed the hypertrophy. These data demonstrate that increased calcineurin-NFAT signalling induces pathological cardiac hypertrophy that is reversed by cyclosporine A. Since the initial discovery, other groups have shown that calcineurin can be activated by hypertrophic signals like angiotensin II, endothelin I and chronic stress (26) and that hypertrophic cardiomyopathy induced by pressure overload can be reversed by cyclosporine A (28). Even with the central role of calcineurin, there are many other molecular signals that are important in the development of hypertrophic cardiomyopathy (26).
Role of Epigenetics in Immunity and Immune Response to Vaccination
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
For instance, in T cells the activity of the transcription factor, nuclear factor of activated T cells (NFAT), is inhibited by the lncRNA, noncoding repressor of NFAT (NRON). This results in the suppression of IL-2 production (Willingham et al. 2005). In another study, Wang et al. have shown that lnc-DC activates STAT3 while also blocking its dephosphorylation and contributes to differentiation of DCs (Wang et al. 2014).
Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
The most important pathways in osteoclastogenesis are (a) IKK/NF-κB and (b) calcineurin/NFATc1. RANK's binding to TRAF 6 results in the activation of NF-κB and its transition to the nucleus. NF-κB induces the expression of the transcription factor c-Fos. NF-κB and c-Fos interact with NFATc1 and thus promote the transcription of genes implicated in osteoclastogenesis. NFATc1 plays a significant role in the modulation of osteoclastogenesis (170). The bisphosphorylation of calcineurin is calcium dependent and also leads to the activation of NFATc1. C-Fos and RNA polymerase II contribute to the increase of the NFATc1 activation (171) (Figure 2.2b).
Andrographolide contributes to the attenuation of cardiac hypertrophy by suppressing endoplasmic reticulum stress
Published in Pharmaceutical Biology, 2023
Qingxin Tian, Jianlong Liu, Qin Chen, Mingxiao Zhang
Cardiac hypertrophy refers to a response of the heart to augmented workload, such as dilated cardiomyopathy, aortic stenosis and hypertension (Myers et al. 2017). Pathological cardiac hypertrophy is characterized by enlarged cardiomyocytes and obstructed contractility of the heart, accompanied by internal changes in cardiomyocytes, including apoptosis, cardiac fibrosis, metabolism and gene expression (Tham et al. 2015; Gesmundo et al. 2017). In the case of coronary artery disease, valvular heart disease and hypertension, the heart may also become hypertrophic under chronic stress or volume overload (Weeks and McMullen 2011). Moreover, cardiac hypertrophy has been reported to usually develop into heart failure (Shimizu and Minamino 2016). Several researchers have clarified that multiple signalling pathways are involved in the occurrence of cardiac hypertrophy, such as typical G protein-coupled receptor (GPCR) and calcineurin-activated T nuclear factor (NFAT) signalling pathways (Madukwe et al. 2018; Zhang et al. 2020). Nevertheless, the mortality from heart failure remains high due to the complex mechanism of the transition from hypertrophy to heart failure, as well as the difficulty of reversing cardiac hypertrophy. Therefore, it is urgent to find a new pharmacological drug that can suppress the progression of cardiac hypertrophy.
Effects of potassium channel knockdown on peripheral blood T lymphocytes and NFAT signaling pathway in Xinjiang Kazak patients with hypertension
Published in Clinical and Experimental Hypertension, 2023
Chen Dai, Meng Tan, Xiaopan Meng, Jian Dong, Yuanming Zhang
Previous studies have demonstrated that the potassium channels and nuclear factor of activated T cells (NFAT) are closely related to the T lymphocyte activation (17,18). There are two major types of membrane ion channels on T lymphocytes, namely the voltage-gated potassium channels (Kv1.3) and calcium-activated potassium channels (KCa3.1) (19). These channels help maintain membrane potential by mediating the outflow of potassium, while the altered membrane potential would indirectly affect the calcium signaling within the cells (20). Therefore, the potassium channels on T lymphocytes are closely related to the intracellular Ca2+ regulation. Calcium is an important second messenger associated with the NFAT signaling pathway. Increased Ca2+ concentration can activate the calcineurin (CaN), which triggers the T lymphocyte activation through NFAT signaling pathway (21) 1. The NFAT signaling pathway can also mediate the lymphocyte proliferation and differentiation. Furthermore, NFAT would activate the production of cytokines, including the tumor necrosis factor-α, IL-4, IL-6, and IFN-β (22). Whether the potassium channels are involved in the occurrence of inflammatory state in the body through the NFAT signaling pathway remains to be elucidated.
A polypeptide inhibitor of calcineurin blocks the calcineurin-NFAT signalling pathway in vivo and in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ping Wang, Wenying Li, Yumeng Yang, Na Cheng, Yuchen Zhang, Nan Zhang, Yanxia Yin, Li Tong, Zhimei Li, Jing Luo
Calcineurin (CN) is a serine/threonine protein phosphatase. It is widely distributed in various tissues, especially in nerve tissues and lymphocytes1,2. CN is a heterodimer composed of the catalytic subunit CNA and the regulatory subunit CNB. Its activity is regulated by Ca2+ and calmodulin (CaM). CN has a variety of substrates and plays an important role in various processes, including the immune response, autophagy and other biological systems3. T cell activating transcription factor (NFAT) is one of the substrates of CN. NFAT plays an important role in the development, activation and function of the immune system. In addition to T cells, NFAT is also expressed in a variety of other immune cells, regulating the expression of a variety of cytokines, such as IL-2, IL-3 and TNF α4.