Coordination of Focal Adhesion Nanoarchitecture and Dynamics in Mechanosensing for Cardiomyoblast Differentiation.

Focal adhesions (FAs) are force-bearing multiprotein complexes, whose nanoscale organization and signaling are essential for cell growth and differentiation. However, the specific organization of FA components to exert spatiotemporal activation of FA proteins for force sensing and transduction remains unclear. In this study, we unveil the intricacies of FA protein nanoarchitecture and that its dynamics are coordinated by a molecular scaffold protein, BNIP-2, to initiate downstream signal transduction for cardiomyoblast differentiation.

The Role Played by Transcription Factor E3 in Modulating Cardiac Hypertrophy.

Transcription factor E3 (TFE3), which is a key regulator of cellular adaptation, is expressed in most tissues, including the heart, and is reportedly overexpressed during cardiac hypertrophy. In this study, TFE3's role in cardiac hypertrophy was investigated. To understand TFE3's physiological importance in cardiac hypertrophy, pressure-overload cardiac hypertrophy was induced through transverse aortic constriction (TAC) in both wild-type (WT) and TFE3 knockout mice (TFE3).

Transposable elements that have recently been mobile in the human genome.

Background: Transposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease. Despite their abovementioned significance, there is no consensus on the TE subfamilies that remain active in the human genome. In this study, we therefore developed a novel statistical test for recently mobile subfamilies (RMSs), based on patterns of overlap with > 100,000 polymorphic indels.

Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes.

Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models.

Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy.

Circular RNAs (circRNAs) sequester microRNAs (miRNAs) and repress their endogenous activity. We hypothesized that artificial circRNA sponges (circmiRs) can be constructed to target miRNAs therapeutically, with a low dosage requirement and extended half-lives compared to current alternatives. This could present a new treatment approach for critical global pathologies, including cardiovascular disease.

Persistent changes in liver methylation and microbiome composition following reversal of diet-induced non-alcoholic-fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that is thought to be reversible by changing the diet. To examine the impact of dietary changes on progression and cure of NAFLD, we fed mice a high-fat diet (HFD) or high-fructose diet (HFrD) for 9 weeks, followed by an additional 9 weeks, where mice were given normal chow diet. As predicted, the diet-induced NAFLD elicited changes in glucose tolerance, serum cholesterol, and triglyceride levels in both diet groups.

Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats.

Background: Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO).

FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy.

Background: Congestive heart failure (CHF) is a significant health care burden in developed countries. However, the molecular events leading from cardiac hypertrophy to CHF are unclear and preventive therapeutic approaches are limited. We have previously described that microphthalmia-associated transcription factor (MITF) is a key regulator of cardiac hypertrophy, but its cardiac targets are still uncharacterized.

Circulating miR-323-3p and miR-652: candidate markers for the presence and progression of acute coronary syndromes.

Background: The prognostic utility of circulating plasma microRNA in patients with acute coronary syndromes (ACS) has been proposed but not yet demonstrated. We set out to investigate circulating microRNA levels in patients incurring recent ACS and examined associations with neurohormones, cardiac structure and function, and survival over 5 years of follow-up.

Methods: An initial screen of 375 microRNAs was performed in 35 ACS patients and 16 healthy controls.

Erbin is a negative modulator of cardiac hypertrophy.

ErbB2 interacting protein (Erbin) is a widely expressed protein and participates in inhibition of several intracellular signaling pathways. Its mRNA has been found to be present in relatively high levels in the heart. However, its physiological role in the heart has not been explored.

Distinct epigenomic features in end-stage failing human hearts.

Background: The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist.

Methods And Results: We constructed genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation (H3K36me3) enrichment for cardiomyopathic and normal human hearts.

Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure.

Epigenetic mechanisms such as microRNA and histone modification are crucially responsible for dysregulated gene expression in heart failure. In contrast, the role of DNA methylation, another well-characterized epigenetic mark, is unknown. In order to examine whether human cardiomyopathy of different etiologies are connected by a unifying pattern of DNA methylation pattern, we undertook profiling with ischaemic and idiopathic end-stage cardiomyopathic left ventricular (LV) explants from patients who had undergone cardiac transplantation compared to normal control.

PKB/Akt activation inhibits p53-mediated HIF1A degradation that is independent of MDM2.

Cross-talk between the two transcription factors, p53 and hypoxia inducible factor 1alpha (HIF1A), is important in different pathophysiological conditions (Hammond and Giaccia, 2006, Clin Cancer Res 12:5007-5009) such as in the transition from myocardial hypertrophy to cardiac dilatation and heart failure. In that context, p53 induces HIF1A degradation which in turn provokes the transition from compensatory hypertrophy to myocardial thinning and chamber dilatation (Sano et al., 2007, Nature 446:444-448).

Elevated InsP3R expression underlies enhanced calcium fluxes and spontaneous extra-systolic calcium release events in hypertrophic cardiac myocytes.

Cardiac hypertrophy is associated with profound remodeling of Ca(2+) signaling pathways. During the early, compensated stages of hypertrophy, Ca(2+) fluxes may be enhanced to facilitate greater contraction, whereas as the hypertrophic heart decompensates, Ca(2+) homeostatic mechanisms are dysregulated leading to decreased contractility, arrhythmia and death. Although ryanodine receptor Ca(2+) release channels (RyR) on the sarcoplasmic reticulum (SR) intracellular Ca(2+) store are primarily responsible for the Ca(2+) flux that induces myocyte contraction, a role for Ca(2+) release via the inositol 1,4,5-trisphosphate receptor (InsP(3)R) in cardiac physiology has also emerged.

Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy.

Cardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca(2+) signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca(2+) fluxes significantly impact on cardiac output and facilitate the development of arrhythmias.

Regulation of p53 tetramerization and nuclear export by ARC.

Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells.

Simplified apoptotic cascades.

Apoptosis is an evolutionarily conserved mode of cell death that is tightly regulated and critical for multicellular organism development and cellular homeostasis. Specific biochemical and morphological changes characterise cells undergoing apoptosis, and reflect the specificity in which activated apoptotic pathways follow. The two best-characterized apoptotic pathways are the extrinsic pathway and the intrinsic pathway, which involve cell surface death receptors and the mitochondria and endoplasmic reticulum respectively.

Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2.

Current evidence shows that cardiomyocyte apoptosis plays a central role in the pathogenesis of myocardial disease and that reactive oxygen species is critically responsible for mediating cardiomyocyte apoptosis in both ischemia-reperfusion injury and dilated cardiomyopathy. ARC (Apoptosis Repressor with Caspase recruitment domain) is an anti-apoptotic protein that is found abundantly in terminally differentiated cells such as cardiomyocytes. The ARC knock-out mouse developed larger infarct in response to ischemia-reperfusion and transitioned more rapidly and severely to dilated cardiomyopathy following aortic constriction.

The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant.

Efficient induction of apoptosis requires not only the activation of death-promoting proteins but also the inactivation of inhibitors of cell death. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both central apoptosis pathways. Despite its potent inhibition of cell death, cells that express abundant ARC eventually succumb.

Death begets failure in the heart.

Recently, low--but abnormal--rates of cardiomyocyte apoptosis have been observed in failing human hearts. Genetic and pharmacological studies suggest that this cell death is causally linked to heart failure in rodent models. Herein, we review these data and discuss potential therapeutic implications.