Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF.

Background: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes HFD+L-NAME (ad libitum high-fat diet and 0.5% N[ω]-nitro-L-arginine methyl ester), we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME.

Transverse aortic constriction multi-omics analysis uncovers pathophysiological cardiac molecular mechanisms.

Time-course multi-omics data of a murine model of progressive heart failure (HF) induced by transverse aortic constriction (TAC) provide insights into the molecular mechanisms that are causatively involved in contractile failure and structural cardiac remodelling. We employ Illumina-based transcriptomics, Nanopore sequencing and mass spectrometry-based proteomics on samples from the left ventricle (LV) and right ventricle (RV, RNA only) of the heart at 1, 7, 21 and 56 days following TAC and Sham surgery. Here, we present Transverse Aortic COnstriction Multi-omics Analysis (TACOMA), as an interactive web application that integrates and visualizes transcriptomics and proteomics data collected in a TAC time-course experiment.

Ca2+/calmodulin-dependent kinase IIδC-induced chronic heart failure does not depend on sarcoplasmic reticulum Ca2+ leak.

Aims: Hyperactivity of Ca/calmodulin-dependent protein kinase II (CaMKII) has emerged as a central cause of pathologic remodelling in heart failure. It has been suggested that CaMKII-induced hyperphosphorylation of the ryanodine receptor 2 (RyR2) and consequently increased diastolic Ca leak from the sarcoplasmic reticulum (SR) is a crucial mechanism by which increased CaMKII activity leads to contractile dysfunction. We aim to evaluate the relevance of CaMKII-dependent RyR2 phosphorylation for CaMKII-induced heart failure development in vivo.

The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions.

Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Mice overexpressing transcription factor Fosl-2 (Fosl-2) represent animal model of SSc. Fosl-2 mice showed interstitial cardiac fibrosis, disorganized connexin-43/40 in intercalated discs and deregulated expression of genes controlling conduction system, and developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability.

CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2.

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle.

Deep phenotyping of two preclinical mouse models and a cohort of RBM20 mutation carriers reveals no sex-dependent disease severity in cardiomyopathy.

cardiomyopathy is an arrhythmogenic form of dilated cardiomyopathy caused by mutations in the splicing factor RBM20. A recent study found a more severe phenotype in male patients with cardiomyopathy patients than in female patients. Here, we aim to determine sex differences in an animal model of cardiomyopathy and investigate potential underlying mechanisms.

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality.

Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice.

Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha-adrenoceptors to early cardiac stress responses.

Hyperactivity of the sympathetic nervous system is a major driver of cardiac remodeling, exerting its effects through both α-, and β-adrenoceptors (α-, β-ARs). As the relative contribution of subtype α-AR to cardiac stress responses remains poorly investigated, we subjected mice to either subcutaneous perfusion with the β-AR agonist isoprenaline (ISO, 30 mg/kg × day) or to a combination of ISO and the stable α-AR agonist phenylephrine (ISO/PE, 30 mg/kg × day each). Telemetry analysis revealed similar hemodynamic responses under both ISO and ISO/PE treatment i.

Ketone body oxidation increases cardiac endothelial cell proliferation.

Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets.

Adaptive versus maladaptive cardiac remodelling in response to sustained β-adrenergic stimulation in a new 'ISO on/off model'.

On the one hand, sustained β-adrenergic stress is a hallmark of heart failure (HF) and exerts maladaptive cardiac remodelling. On the other hand, acute β-adrenergic stimulation maintains cardiac function under physiological stress. However, it is still incompletely understood to what extent the adaptive component of β-adrenergic signaling contributes to the maintenance of cardiac function during chronic β-adrenergic stress.

Loss of CASK Accelerates Heart Failure Development.

[Figure: see text].

CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy.

Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs, including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications; instead, other diabetes-related alterations could be causative.

Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis.

Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT).

Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control.

Aims: Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias.

The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts and as a serine protease cleaving HDAC4.

CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation.

Sympathetic activation of β-adrenoreceptors (β-AR) represents a hallmark in the development of heart failure (HF). However, little is known about the underlying mechanisms of gene regulation. In human ventricular myocardium from patients with end-stage HF, we found high levels of phosphorylated histone 3 at serine-28 (H3S28p).

O-GlcNAcylation of Histone Deacetylase 4 Protects the Diabetic Heart From Failure.

Background: Worldwide, diabetes mellitus and heart failure represent frequent comorbidities with high socioeconomic impact and steadily growing incidence, calling for a better understanding of how diabetic metabolism promotes cardiac dysfunction. Paradoxically, some glucose-lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling. Here, we identified a histone deacetylase 4 (HDAC4) subdomain as a molecular checkpoint of adaptive and maladaptive signaling in the diabetic heart.

CaMKII does not control mitochondrial Ca uptake in cardiac myocytes.

Key Points: Mitochondrial Ca uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH ) required for ATP production and reactive oxygen species (ROS) elimination. Ca /calmodulin-dependent protein kinase II (CaMKII) has been proposed to regulate mitochondrial Ca uptake via mitochondrial Ca uniporter phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ knockout) or cardiomyocyte-specific deletion of CaMKIIδ and γ (CaMKIIδ/γ double knockout) to interrogate whether CaMKII controls mitochondrial Ca uptake in isolated mitochondria and during β-adrenergic stimulation in cardiac myocytes.

A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.

The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP).

Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4.

Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. However, many cardiac effects of atropine cannot be adequately explained solely by its antagonism at muscarinic receptors. In isolated mouse ventricular cardiomyocytes expressing a Förster resonance energy transfer (FRET)-based cAMP biosensor, we confirmed that atropine inhibited acetylcholine-induced decreases in cAMP.

Calcium Signaling and Transcriptional Regulation in Cardiomyocytes.

Calcium (Ca) is a universal regulator of various cellular functions. In cardiomyocytes, Ca is the central element of excitation-contraction coupling, but also impacts diverse signaling cascades and influences the regulation of gene expression, referred to as excitation-transcription coupling. Disturbances in cellular Ca-handling and alterations in Ca-dependent gene expression patterns are pivotal characteristics of failing cardiomyocytes, with several excitation-transcription coupling pathways shown to be critically involved in structural and functional remodeling processes.

Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure.

Background: Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF.

Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity.

Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias.