Reversible lysine fatty acylation of an anchoring protein mediates adipocyte adrenergic signaling.

N-myristoylation on glycine is an irreversible modification that has long been recognized to govern protein localization and function. In contrast, the biological roles of lysine myristoylation remain ill-defined. We demonstrate that the cytoplasmic scaffolding protein, gravin-α/A kinase-anchoring protein 12, is myristoylated on two lysine residues embedded in its carboxyl-terminal protein kinase A (PKA) binding domain. Histone deacetylase 11 (HDAC11) docks to an adjacent region of gravin-α and demyristoylates these sites. In brown and white adipocytes, lysine myristoylation of gravin-α is required for signaling via ß2- and ß3-adrenergic receptors (ß-ARs), which are G protein-coupled receptors (GPCRs). Lysine myristoylation of gravin-α drives ß-ARs to lipid raft membrane microdomains, which results in PKA activation and downstream signaling that culminates in protective thermogenic gene expression. These findings define reversible lysine myristoylation as a mechanism for controlling GPCR signaling and highlight the potential of inhibiting HDAC11 to manipulate adipocyte phenotypes for therapeutic purposes.

Societal costs of untreated perinatal mood and anxiety disorders in Vermont.

PURPOSE: To estimate the societal costs of untreated perinatal mood and anxiety disorders (PMADs) in Vermont for the 2018-2020 average annual birth cohort from conception through five years postpartum. METHODS: We developed a cost analysis model to calculate the excess cases of outcomes attributed to PMADs in the state of Vermont. Then, we modeled the associated costs of each outcome incurred by birthing parents and their children, projected five years for birthing parents who do not achieve remission by the end of the first year postpartum. RESULTS: We estimated that the total societal cost of untreated PMADs in Vermont could reach $48 million for an annual birth cohort from conception to five years postpartum, amounting to $35,910 in excess societal costs per birthing parent with an untreated PMAD and their child. CONCLUSION: Our model provides evidence of the high costs of untreated PMADs for birthing parents and their children in Vermont. Our estimates for Vermont are slightly higher but comparable to national estimates, which are $35,500 per birthing parent-child pair, adjusted to 2021 US dollars. Investing in perinatal mental health prevention and treatment could improve health outcomes and reduce economic burden of PMADs on individuals, families, employers, and the state.

Integration of epigenetic regulatory mechanisms in heart failure.

The number of "omics" approaches is continuously growing. Among others, epigenetics has appeared as an attractive area of investigation by the cardiovascular research community, notably considering its association with disease development. Complex diseases such as cardiovascular diseases have to be tackled using methods integrating different omics levels, so called "multi-omics" approaches. These approaches combine and co-analyze different levels of disease regulation. In this review, we present and discuss the role of epigenetic mechanisms in regulating gene expression and provide an integrated view of how these mechanisms are interlinked and regulate the development of cardiac disease, with a particular attention to heart failure. We focus on DNA, histone, and RNA modifications, and discuss the current methods and tools used for data integration and analysis. Enhancing the knowledge of these regulatory mechanisms may lead to novel therapeutic approaches and biomarkers for precision healthcare and improved clinical outcomes.

Regulatory RNAs in Heart Failure.

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.

DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy.

Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling.NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.

Contractile responses to endothelin-1 are regulated by PKC phosphorylation of cardiac myosin binding protein-C in rat ventricular myocytes.

The shortening of sarcomeres that co-ordinates the pump function of the heart is stimulated by electrically-mediated increases in [Ca2+]. This process of excitation-contraction coupling (ECC) is subject to modulation by neurohormonal mediators that tune the output of the heart to meet the needs of the organism. Endothelin-1 (ET-1) is a potent modulator of cardiac function with effects on contraction amplitude, chronotropy and automaticity. The actions of ET-1 are evident during normal adaptive physiological responses and increased under pathophysiological conditions, such as following myocardial infarction and during heart failure, where ET-1 levels are elevated. In myocytes, ET-1 acts through ETA- or ETB-G protein-coupled receptors (GPCRs). Although well studied in atrial myocytes, the influence and mechanisms of action of ET-1 upon ECC in ventricular myocytes are not fully resolved. We show in rat ventricular myocytes that ET-1 elicits a biphasic effect on fractional shortening (initial transient negative and sustained positive inotropy) and increases the peak amplitude of systolic Ca2+ transients in adult rat ventricular myocytes. The negative inotropic phase was ETB receptor-dependent, whereas the positive inotropic response and increase in peak amplitude of systolic Ca2+ transients required ETA receptor engagement. Both effects of ET-1 required phospholipase C (PLC)-activity, although distinct signalling pathways downstream of PLC elicited the effects of each ET receptor. The negative inotropic response involved inositol 1,4,5-trisphosphate (InsP3) signalling and protein kinase C epsilon (PKCε). The positive inotropic action and the enhancement in Ca2+ transient amplitude induced by ET-1 were independent of InsP3 signalling, but suppressed by PKCε. Serine 302 in cardiac myosin binding protein-C was identified as a PKCε substrate that when phosphorylated contributed to the suppression of contraction and Ca2+ transients by PKCε following ET-1 stimulation. Thus, our data provide a new role and mechanism of action for InsP3 and PKCε in mediating the negative inotropic response and in restraining the positive inotropy and enhancement in Ca2+ transients following ET-1 stimulation.

Hydrological droughts in the 21st century, hotspots and uncertainties from a global multimodel ensemble experiment.

Increasing concentrations of greenhouse gases in the atmosphere are expected to modify the global water cycle with significant consequences for terrestrial hydrology. We assess the impact of climate change on hydrological droughts in a multimodel experiment including seven global impact models (GIMs) driven by bias-corrected climate from five global climate models under four representative concentration pathways (RCPs). Drought severity is defined as the fraction of land under drought conditions. Results show a likely increase in the global severity of hydrological drought at the end of the 21st century, with systematically greater increases for RCPs describing stronger radiative forcings. Under RCP8.5, droughts exceeding 40% of analyzed land area are projected by nearly half of the simulations. This increase in drought severity has a strong signal-to-noise ratio at the global scale, and Southern Europe, the Middle East, the Southeast United States, Chile, and South West Australia are identified as possible hotspots for future water security issues. The uncertainty due to GIMs is greater than that from global climate models, particularly if including a GIM that accounts for the dynamic response of plants to CO2 and climate, as this model simulates little or no increase in drought frequency. Our study demonstrates that different representations of terrestrial water-cycle processes in GIMs are responsible for a much larger uncertainty in the response of hydrological drought to climate change than previously thought. When assessing the impact of climate change on hydrology, it is therefore critical to consider a diverse range of GIMs to better capture the uncertainty.

The importance of community-specific survey data in understanding behavioral and social drivers of COVID-19 vaccination: Lessons learned from urban neighborhoods in four United States cities.

This descriptive study examined patterns and trends in coronavirus (COVID-19) vaccination rates and drivers among people living, working, or socializing in urban neighborhoods of predominantly Black and Hispanic communities and compared them with the results of two national surveys. Data for these communities came from a routine survey conducted as part of the Equity-first Vaccination Initiative (EVI) in urban neighborhoods within four United States (U.S.) cities during four phases of the pandemic between July 2021 and April 2022. Our sample included 5,970 responses, which were weighted to account for design effects and compositional differences among surveyed people across the four periods. We wanted to compare the results from the EVI survey to nationally representative surveys, therefore, we did not demographically weight the sample to look like the national surveys. As a result, the EVI survey included larger proportions of people identifying with non-white racial and ethnic groups than those groups' proportions of the national population per the last U.S. Census (African American or Black: 49.8% vs. 13.7%, Hispanic or Latino/Latinx 36.5% vs. 18.9%, respectively). More EVI respondents reported concern about vaccines and fewer reported trust in COVID-19 information key messengers than national averages. The EVI survey found variation in the proportions as well as the magnitude and directionality of increases or decreases in beliefs about vaccination safety and effectiveness, the influence of religious beliefs, and intentions to get vaccinated. These differences highlight the granular insight that community-specific data can help better tailor interventions to communities disproportionately impacted by disease.

Fat-to-heart crosstalk in health and disease.

According to the latest World Health Organization statistics, cardiovascular disease (CVD) is one of the leading causes of death globally. Due to the rise in the prevalence of major risk factors, such as diabetes mellitus and obesity, the burden of CVD is expected to worsen in the decades to come. Whilst obesity is a major and consistent risk factor for CVD, the underlying pathological molecular communication between peripheral fat depots and the heart remains poorly understood. Adipose tissue (AT) is a major endocrine organ in the human body, with composite cells producing and secreting hormones, cytokines, and non-coding RNAs into the circulation to alter the phenotype of multiple organs, including the heart. Epicardial AT (EAT) is an AT deposit that is in direct contact with the myocardium and can therefore influence cardiac function through both mechanical and molecular means. Moreover, resident and recruited immune cells comprise an important adipose cell type, which can create a pro-inflammatory environment in the context of obesity, potentially contributing to systemic inflammation and cardiomyopathies. New mechanisms of fat-to-heart crosstalk, including those governed by non-coding RNAs and extracellular vesicles, are being investigated to deepen the understanding of this highly common risk factor. In this review, molecular crosstalk between AT and the heart will be discussed, with a focus on endocrine and paracrine signaling, immune cells, inflammatory cytokines, and inter-organ communication through non-coding RNAs.

Hybrid Microsurgical Breast Reconstruction:: HyFIL® & HyPAD™ Techniques.

There are numerous indications for hybrid breast reconstruction, with the most common being patients who have inadequate donor site volume to achieve the desired breast volume. This article reviews all aspects of hybrid breast reconstruction, including preoperative and assessment, operative technique and considerations, and postoperative management.

HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance.

Stimulation of adipocyte ß-adrenergic receptors (ß-ARs) induces expression of uncoupling protein 1 (UCP1), promoting nonshivering thermogenesis. Association of ß-ARs with a lysine-myristoylated form of A kinase-anchoring protein 12 (AKAP12, also known as gravin-α) is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of ß-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-α myristoylation-dependent induction of UCP1 protein expression, with a noncanonical acute response that is posttranscriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where ß-AR signaling is blocked. These findings define cell-autonomous, multimodal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of ß-AR stimulation.

HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance.

Stimulation of adipocyte ß-adrenergic receptors (ß-ARs) induces expression of uncoupling protein 1 (UCP1), promoting non-shivering thermogenesis. Association of ß-ARs with a lysine myristoylated form of A-kinase anchoring protein 12 (AKAP12)/gravin-α is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of ß-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-α myristoylation-dependent induction of UCP1 protein expression, with a non-canonical acute response that is post-transcriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where ß-AR signaling is blocked. These findings define cell autonomous, multi-modal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of ß-AR stimulation.

Differential expression of epigenetic modifiers in early and late cardiotoxic heart failure reveals DNA methylation as a key regulator of cardiotoxicity.

Background: Anthracycline-induced cardiotoxicity is a well-known serious clinical entity. However, detailed mechanistic insights on how short-term administration leads to late and long-lasting cardiotoxicity, are still largely undiscovered. We hypothesize that chemotherapy provokes a memory effect at the level of epigenomic DNA modifications which subsequently lead to cardiotoxicity even years after cessation of chemotherapy. Methods: We explored the temporal evolution of epigenetic modifiers in early and late cardiotoxicity due to anthracyclines by means of RNA-sequencing of human endomyocardial left ventricular biopsies and mass spectrometry of genomic DNA. Based on these findings, validation of differentially regulated genes was obtained by performing RT-qPCR. Finally, a proof-of-concept in vitro mechanistic study was performed to dissect some of the mechanistic aspects of epigenetic memory in anthracycline-induced cardiotoxicity. Results: Correlation of gene expression between late and early onset cardiotoxicity revealed an R 2 value of 0.98, demonstrating a total of 369 differentially expressed genes (DEGs, FDR < 0.05). of which 72% (n = 266) were upregulated, and 28% of genes, (n = 103) downregulated in later as compared to earlier onset cardiotoxicity. Gene ontology analysis showed significant enrichment of genes involved in methyl-CpG DNA binding, chromatin remodeling and regulation of transcription and positive regulation of apoptosis. Differential mRNA expression of genes involved in DNA methylation metabolism were confirmed by RT-qPCR in endomyocardial biopsies. In a larger biopsy cohort, it was shown that Tet2 was more abundantly expressed in cardiotoxicity biopsies vs. control biopsies and vs. non-ischemic cardiomyopathy patients. Moreover, an in vitro study was performed: following short-term doxorubicin treatment, H9c2 cells were cultured and passaged once they reached a confluency of 70%-80%. When compared to vehicle-only treated cells, in doxorubicin-treated cells, three weeks after short term treatment, Nppa, Nppb, Tet1/2 and other genes involved in active DNA demethylation were markedly upregulated. These alterations coincided with a loss of DNA methylation and a gain in hydroxymethylation, reflecting the epigenetic changes seen in the endomyocardial biopsies. Conclusions: Short-term administration of anthracyclines provokes long-lasting epigenetic modifications in cardiomyocytes both in vivo and in vitro, which explain in part the time lapse between the use of chemotherapy and the development of cardiotoxicity and, eventually, heart failure.

Inducible apelin receptor knockdown reduces differentiation efficiency and contractility of hESC-derived cardiomyocytes.

AIMS: The apelin receptor, a G protein-coupled receptor, has emerged as a key regulator of cardiovascular development, physiology, and disease. However, there is a lack of suitable human in vitro models to investigate the apelinergic system in cardiovascular cell types. For the first time we have used human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and a novel inducible knockdown system to examine the role of the apelin receptor in both cardiomyocyte development and to determine the consequences of loss of apelin receptor function as a model of disease. METHODS AND RESULTS: Expression of the apelin receptor and its ligands in hESCs and hESC-CMs was determined. hESCs carrying a tetracycline-inducible short hairpin RNA targeting the apelin receptor were generated using the sOPTiKD system. Phenotypic assays characterized the consequences of either apelin receptor knockdown before hESC-CM differentiation (early knockdown) or in 3D engineered heart tissues as a disease model (late knockdown). hESC-CMs expressed the apelin signalling system at a similar level to the adult heart. Early apelin receptor knockdown decreased cardiomyocyte differentiation efficiency and prolonged voltage sensing, associated with asynchronous contraction. Late apelin receptor knockdown had detrimental consequences on 3D engineered heart tissue contractile properties, decreasing contractility and increasing stiffness. CONCLUSIONS: We have successfully knocked down the apelin receptor, using an inducible system, to demonstrate a key role in hESC-CM differentiation. Knockdown in 3D engineered heart tissues recapitulated the phenotype of apelin receptor down-regulation in a failing heart, providing a potential platform for modelling heart failure and testing novel therapeutic strategies.

COVID-19 and BRD4: a stormy and cardiotoxic bromo-romance.

Severe systemic inflammation in COVID-19 patients can lead to dysfunction of multiple organs, including the heart. Using an ex vivo cardiac organoid system, Mills et al discovered that inhibitors of the chromatin reader protein, bromodomain-containing protein 4, protect cardiomyocytes from COVID-associated "cytokine storm". We briefly review these important findings and highlight the translational significance of the work.

Noncoding RNAs in age-related cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the adult population worldwide and represent a severe economic burden and public health concern. The majority of human genes do not code for proteins. However, noncoding transcripts play important roles in ageing that significantly increases the risk for CVDs. Noncoding RNAs (ncRNAs) are critical regulators of multiple biological processes related to ageing such as oxidative stress, mitochondrial dysfunction and chronic inflammation. NcRNAs are also involved in pathophysiological developments within the cardiovascular system including arrhythmias, cardiac hypertrophy, fibrosis, myocardial infarction and heart failure. In this review article, we cover the roles of ncRNAs in cardiovascular ageing and disease as well as their potential therapeutic applications in CVDs.