Epac is a guanine nucleotide exchange protein that is directly activated by cAMP, but whose cardiac cellular functions remain unclear. It is important to understand cardiac Epac signaling, because it is activated in parallel to classical cAMP-dependent signaling via protein kinase A. In addition to activating contraction, Ca2+ is a key cardiac transcription regulator (excitation-transcription coupling). It is unknown how myocyte Ca2+ signals are decoded in cardiac myocytes to control nuclear transcription. We examine Epac actions on cytosolic ([Ca2+]i) and intranuclear ([Ca2+]n) Ca2+ homeostasis, focusing on whether Epac alters [Ca2+]n and activates a prohypertrophic program in cardiomyocytes. Adult rat cardiomyocytes, loaded with fluo-3 were viewed by confocal microscopy during electrical field stimulation at 1 Hz. Acute Epac activation by 8-pCPT increased Ca2+ sparks and diastolic [Ca2+]i, but decreased systolic [Ca2+]i. The effects on diastolic [Ca2+]i and Ca2+ spark frequency were dependent on phospholipase C (PLC), inositol 1,3,5 triphosphate receptor (IP3R) and CaMKII activation. Interestingly, Epac preferentially increased [Ca2+]n during both diastole and systole, correlating with the perinuclear expression pattern of Epac. Moreover, Epac activation induced histone deacetylase 5 (HDAC5) nuclear export, with consequent activation of the prohypertrophic transcription factor MEF2. These data provide the first evidence that the cAMP-binding protein Epac modulates cardiac nuclear Ca2+ signaling by increasing [Ca2+]n through PLC, IP3R and CaMKII activation, and initiates a prohypertrophic program via HDAC5 nuclear export and subsequent activation of the transcription factor MEF2.

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Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. Prolongation of the action potential duration and downregulation of several K(+) currents might participate in the genesis of arrhythmias associated with chronic heart failure. Little information is available related to the mechanism by which TNF-alpha modulates cardiac K(+) channels. The present study analyzes the effect of TNF-alpha on the transient outward K(+) current (I(to)) in rat ventricular myocytes, using the whole cell patch-clamp technique. We found that TNF-alpha is able to induce a significant reduction of I(to) density, modifies its inactivation, and downregulates the Kv4.2 protein expression, while calcium current density is not affected. We have also demonstrated that the reduction of I(to) density induced by TNF-alpha was prevented by the selective inducible nitric oxide synthase (iNOS) inhibitor 1400-W, the protein synthesis inhibitor cycloheximide, the antioxidant tocopherol, and the superoxide dismutase mimetic manganese(III) tetrakis (4-benzoic acid) porphyrin. In addition, a reduced I(to) density was recorded in ventricular myocytes exposed to peroxynitrite, supporting a possible participation of this oxidant in the effects of TNF-alpha on I(to). We conclude that TNF-alpha exposure, through iNOS induction and generation of oxidant species, promotes electrophysiological changes (decreased I(to) and action potential duration prolongation) in rat ventricular myocytes, providing new insights into how cytokines modulate K(+) channels in the heart.

Endothelial dysfunction caused by HFD is related to a dysfunctional endothelial AMPK-PI3K-Akt-eNOS pathway correlating with the increase of plasma NEFA, TG, and an impaired glucose management.

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Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect.

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