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Role of Krüppel-Like Factors in Endothelial Cell Function and Shear Stress–Mediated Vasoprotection
Published in Juhyun Lee, Sharon Gerecht, Hanjoong Jo, Tzung Hsiai, Modern Mechanobiology, 2021
Statins (3-hydroxy-3-methylglutaryl coenzyme A inhibitors) are widely used in the treatment of dyslipidemia [115]. As demonstrated by basic and clinical studies, statins also have pleiotropic effects apart from lowering cholesterol, including anti-inflammatory and antithrombotic effects. As demonstrated in the JUPITER trial, treatment of patients with evidence of clinical inflammation based on elevated high-sensitivity C-reactive protein levels but who were otherwise healthy and without clinical hyperlipidemia using rosuvastatin led to a reduction of cardiovascular events [116]. The effect of statins on endothelial function overlaps with that of KLF2. This fact led us to speculate whether there might be the novel link between KLF2 and statins. Indeed, we and others have demonstrated that multiple statins robustly induce KLF2 in endothelial cells [117, 118]. Importantly, knockdown of KLF2 inhibits statin-mediated eNOS and TM induction, indicating that KLF2 mediates statin effects [117]. Both MEF2 and Rho activity is critical for regulating KLF2 expression by statins. MEF2 directly transactivates the KLF2 promoter. Constitutive Rho activity downregulates KLF2 by geranylgeranyl pyrophosphate–dependent mechanisms [117]. By inhibiting the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, statins lead to the depletion of geranylgeranyl pyrophosphate.
Molecular Mechanisms for Statin Pleiotropy and Possible Clinical Relevance in Cardiovascular Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Brian Yu, Nikola Sladojevic, James K. Liao
Many studies have shown statin-induced improvement of endothelial function occurs before significant decreases in serum cholesterol levels (Anderson et al., 1995; O’Driscoll et al., 1997). These early pleiotropic effects are thought to be caused by increases in endothelial NO production through stabilization and increased expression of endothelial NO synthase (eNOS) mRNA (Laufs and Liao, 1998; Laufs et al., 1998). These effects on eNOS expression are reversed by GGPP and not by FPP or LDL-C, suggesting RhoA inhibition by statins increases eNOS half-life and expression (Laufs et al., 1998). Indeed, ROCK, a major downstream effector of RhoA, has been proposed as an important negative regulator of eNOS activity. For instance, use of dominant negative mutants of ROCK or ROCK inhibitors increases eNOS mRNA half-life and expression (Rikitake et al., 2005). Thus, statins may exert cardioprotective effects by regulation of eNOS transcription. A transcription factor inducted by statins that leads to eNOS mRNA stabilization is the Kuppel-like factor 2 (KLF2), whose activation involves the myocyte enhancer factor 2 (MEF2) (Sen-Banerjee et al., 2005). Further research is necessary to characterize the effect of statins on transcription factors in endothelial function.
Regeneration of Cardiomyocytes from Bone Marrow Stem Cells and Application to Cell Transplantation Therapy
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Various cardiac specific transcription factors have been cloned, and their genes are serially expressed in the developing heart during myogenesis and morphogenesis. Figure 4 shows the time course of the expression of cardiomyocyte-specific transcription factors in fetal developing heart and CMG cells. The genes coding Nkx2.515 (homeobox type transcription factor specifically expressed beginning in the early developing heart), GATA416 (GATA-motif-binding Zinc finger type transcription factor expressed beginning in the early stage developing heart), HAND 1/2 (basic helix-loop-helix type transcription factor expressed in the heart and autonomic nervous system), and MEF2-B/C17 (muscle enhancement factor: a MADS box family transcription factor expressed in the myocytes) were expressed in the early stage of heart development, and MEF2A and MEF2-D in the middle stage. The CMG cells already expressed GATA4, TEF-118(transcription enhancement factor 2), Nkx2.5, HAND, and MEF2-C before exposure to 5-azacytidine, and they expressed MEF2-A and MEF2-D after exposure to 5-azacytidine. This pattern of gene expression in CMG cells was similar to that of developing cardiomyocytes in vivo,11 and indicated that the developmental stage of the undifferentiated CMG cells is close to that of cardiomyoblasts or the early stages of heart development. We estimated that the stage of differentiation of the CMG cells lies between the cardiomyocyte-progenitor stage and the differentiated cardiomyocyte stage.
Myosin heavy chain isoform composition in the deltoid and vastus lateralis muscles of elite handball players
Published in Journal of Sports Sciences, 2020
Athanasios Mandroukas, Thomas I. Metaxas, Zacharoula Papadopoulou, Jan Heller, Nikos V. Margaritelis, Kosmas Christoulas, Bjorn Ekblom, Ioannis S. Vrabas
The underlying mechanisms for the effects of exercise on MHC isoform composition are largely unknown and remain to be elucidated (Pette, 2002). However, calcium homoeostasis and its cellular metabolism seem to be key features for this effect. For instance, calcineurin, a Ca2+/calmodulin-dependent serine/threonine protein phosphatase, activates members of the Nuclear Factor of Activated T-cells (NFAT) family and the MADS-box transcription factor MEF2. NFATs and MEF2, once activated by calcineurin, bind to specific promoters for the transcription of slow fibre type-specific genes (McCullagh et al., 2004; Wu et al., 2000). Calcium-regulation of fibre type transitions also includes the co-operation with other molecules, such as calsarcin and calmodulin-dependent protein kinase, yet, it is beyond the scope of the present work to describe these mechanisms in detail (Pette, 2002).
Redox homeostasis in sport: do athletes really need antioxidant support?
Published in Research in Sports Medicine, 2019
Ambra Antonioni, Cristina Fantini, Ivan Dimauro, Daniela Caporossi
The general consensus is that, depending upon the type, frequency, duration, and intensity of exercise and/or the antioxidant capacity of the individual, ROS production and/or oxidative stress, elicited by exercise, represents stimulus for the transient activation of Stress-Activated Protein Kinase (SAPK) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways. Uncontrolled or sustained activation of these signaling pathways is associated with the development and progression of cancer, neurodegenerative and cardio-metabolic diseases (Muslin, 2008; Valko et al., 2007). Differently, their controlled and/or transient activation is required for normal physiological functioning and it is known that they mediate many of the adaptations and health benefits exerted by regular exercise (Figure 1). As extensively described in referent review articles (Egan & Zierath, 2013; Hawley et al., 2014; Radak et al., 2013), exercise-induced SAPK/MAPK pathways activate important transcription factors such as c-jun, c-fos, p53, nuclear respiratory factor 2 (NFR2), nuclear factor kappa B (NFκB), myocyte-enhancing factor 2 (MEF2), and ETS domain-containing protein Elk-1 (ELK1) as well as coactivators peroxisome proliferator-activated receptor gamma coactivator 1-alpha and 1-beta (PGC-1α/β), most of them described as key regulators of beneficial metabolic changes counteracting the onset of cardio-metabolic diseases. Moreover, the activation of aforementioned signaling pathways is also associated with increased gene expression and the up-regulation of antioxidants defenses such as SOD1/2, CAT and GPx1 (Parker, Shaw, Stepto, & Levinger, 2017), as well as specific proteins related to stress response (Dimauro et al., 2016).