High mobility group box 1 (HMGB1) is a ubiquitous nuclear DNA-binding protein whose function is dependent on its cellular location. Extracellular HMGB1 is regarded as a delayed mediator of proinflammatory cytokines for initiating and amplifying inflammatory responses, whereas nuclear HMGB1 has been found to prevent cardiac hypertrophy and heart failure. Because fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has shown both protective effects against cardiac hypertrophy and inhibitory effects against inflammation, the potential modulation of HMGB1 expression and secretion by fenofibrate is of great interest. We herein provide evidence that fenofibrate modulates basal and LPS-stimulated HMGB1 expression and localization in addition to secretion of HMGB1 in cardiomyocytes. In addition, administration of fenofibrate to mice prevented the development of cardiac hypertrophy induced by thoracic transverse aortic constriction (TAC) while increasing levels of nuclear HMGB1. Altogether, these data suggest that fenofibrate may inhibit the development of cardiac hypertrophy by regulating HMGB1 expression, which provides a new potential strategy to treat cardiac hypertrophy. 1. Introduction High mobility group box 1 (HMGB1), a nuclear DNA-binding protein, is expressed in diverse cell types, including cardiomyocytes [1, 2]. HMGB1 exhibits diverse functions according to its cellular location. In the extracellular compartment, it plays an important role in inflammatory responses when actively secreted from stressed cells [3]. However, in addition to its extracellular functions, intracellular HMGB1 participates in a number of fundamental cellular processes such as transcription, replication, and DNA repair [4, 5]. HMGB1 has been demonstrated to play a pivotal role in cardiovascular disease in different studies [6]. Additionally, maintenance of stable nuclear HMGB1 levels has emerged as a potential treatment for cardiac hypertrophy because HMGB1 overexpression in the nucleus can prevent hypertrophy and heart failure by inhibiting DNA damage [2]. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors belonging to the nuclear receptor superfamily [7]. There are three known PPAR isoforms, , , and , which exhibit tissue-specific distribution and legend-specific effects [8, 9]. In particular, PPAR is abundant in metabolically active tissues, including the liver, brown fat, kidney, skeletal muscle, and heart [10]. In addition to their metabolic roles in the heart, PPAR and its agonist fenofibrate have
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