br Materials and methods br Results br
Materials and methods
Discussion Myocardium reperfusion injury contributes almost half of myocardial infarct size in myocardial infarction patients, and infarct size is closely correlated with the probability of developing Mycophenolic acid failure . Despite this knowledge, myocardial reperfusion injury is largely a missed therapeutic target. Although numerous therapeutic strategies have been developed to mitigate reperfusion injury, no standard therapies are currently available . Enhancing autophagy protects against I/R injury in cardiac myocytes in vitro and in vivo . Furthermore, a recent report shows that cardiomyocyte-specific disruption of autophagy by conditional knockout of ATG7, an essential autophagy-related gene (ATG), leads to severe myocardial dysfunction during I/R injury . Mitochondrial dysfunction has also been shown to play a significant role in inducing myocardial apoptosis during I/R injury . However, it is unclear whether autophagy plays a protective role on mitochondrial homeostasis in cardiomyocytes during I/R injury. Administration of SAHA (HDAC inhibitor) during reperfusion reduces myocardial infarct size through maintaining autophagic flux in a large animal model . Therefore, using SAHA and ATG loss of function as tools, we investigated the role of autophagy in mitochondrial homeostasis in cardiomyocytes during I/R injury.
Conclusion and perspective
Sources of funding This work was supported by a grant from the National Institutes of Health (K08HL127305).
Introduction Atrial fibrillation (AF) is the most common sustained and progressive clinical tachycardia which contributes to cardiovascular morbidity and mortality . AF is characterized by specific electrical, transcriptional and structural changes in the cardiomyocyte, commonly denoted as remodeling . Cardiomyocyte remodeling underlies contractile dysfunction and the progression of AF. Therefore, it is of great interest to dissect the molecular mechanisms underlying cardiomyocyte remodeling, with the aim to identify novel druggable targets which attenuate remodeling and AF progression. Previous research identified that (re)activation of pathological and fetal gene program in cardiomyocytes promotes AF onset and progression [3,4]. Ausma et al. showed upregulation of two proteins of the fetal program in the goat model for AF, i.e. the slow-contracting beta-myosin heavy chain isoform (β-MHC) and smooth muscle α-actin (α-SMA) [, , , ]. In persistent AF patients, numerous fetal/neonatal variants of the titin protein were observed in cardiac myofibrils, and atrial re-expression of TnI-skeletal-slow-twitch (ssTnI) was found in patients with paroxysmal AF . In addition, persistent AF was associated with higher cardiac mRNA expression of brain natriuretic peptide (BNP) . Interestingly, pathological and fetal gene expression is under control of epigenetic regulation [, , , , ]. Hence, epigenetic regulation has been identified as an important mechanism underlying the progression of cardiac diseases [, , , , ]. Epigenetic regulation refers to processes that influence the packaging or processing of nuclear DNA, thus controlling the on/off states of multiple genes with discrete switches. The packaging of chromatin is largely dependent on the acetylation status of histones, which is controlled by histone acetyl transferases and histone deacetylases (HDACs) [, , , , ]. HDACs are an ancient family of enzymes that catalyze the removal of acetyl groups from the ε-amino group of specific acetyl lysine residues within their protein substrates. In general, deacetylation of histones in nucleosomes induces chromatin condensation, which inhibits binding of transcription factors and other components of the transcriptional machinery to gene promoter and enhancer regions, ultimately resulting in transcriptional repression. As such, histone deacetylation serves as an important regulator of gene expression.