Regulation of cardiomyocyte t-tubule structure by preload and afterload: Roles in cardiac compensation and decompensation.

Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles.

Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.

Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation.

Inhibition of the extracellular enzyme A disintegrin and metalloprotease with thrombospondin motif 4 prevents cardiac fibrosis and dysfunction.

Aims: Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis.

Methods And Results: The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload.

Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure.

Background: Increasing SERCA2 (sarco[endo]-plasmic reticulum Ca ATPase 2) activity is suggested to be beneficial in chronic heart failure, but no selective SERCA2-activating drugs are available. PDE3A (phosphodiesterase 3A) is proposed to be present in the SERCA2 interactome and limit SERCA2 activity. Disruption of PDE3A from SERCA2 might thus be a strategy to develop SERCA2 activators.

The female syndecan-4 heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels.

In cardiac muscle, the ubiquitously expressed proteoglycan syndecan-4 is involved in the hypertrophic response to pressure overload. Protein kinase Akt signaling, which is known to regulate hypertrophy, has been found to be reduced in the cardiac muscle of exercised male syndecan-4 mice. In contrast, we have recently found that pSer473-Akt signaling is elevated in the skeletal muscle ( TA) of female syndecan-4 mice.

Regulation of Cardiac Contractility by the Alpha 2 Subunit of the Na/K-ATPase.

Cytosolic Na + concentrations regulate cardiac excitation-contraction coupling and contractility. Inhibition of the Na/K-ATPase (NKA) activity increases cardiac contractility by increasing cytosolic Ca levels, as increased cytosolic Na levels are coupled to less Ca extrusion and/or increased Ca influx from the Na/Ca-exchanger. NKA consists of one α subunit and one β subunit, with α1 and α2 being the main α isoforms in cardiomyocytes.

MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy.

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process.

AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR.

Background: The sarcoplasmic reticulum (SR) Ca-ATPase 2 (SERCA2) mediates Ca reuptake into SR and thereby promotes cardiomyocyte relaxation, whereas the ryanodine receptor (RYR) mediates Ca release from SR and triggers contraction. Ca/CaMKII (CaM [calmodulin]-dependent protein kinase II) regulates activities of SERCA2 through phosphorylation of PLN (phospholamban) and RYR through direct phosphorylation. However, the mechanisms for CaMKIIδ anchoring to SERCA2-PLN and RYR and its regulation by local Ca signals remain elusive.

Design of a Proteolytically Stable Sodium-Calcium Exchanger 1 Activator Peptide for Studies.

The cardiac sodium-calcium exchanger (NCX1) is important for normal Na- and Ca-homeostasis and cardiomyocyte relaxation and contraction. It has been suggested that NCX1 activity is reduced by phosphorylated phospholemman (pSer68-PLM); however its direct interaction with PLM is debated. Disruption of the potentially inhibitory pSer68-PLM-NCX1 interaction might be a therapeutic strategy to increase NCX1 activity in cardiac disease.

CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors.

Aims: Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signalling and compartmentation.

Exercise Training Stabilizes RyR2-Dependent Ca Release in Post-infarction Heart Failure.

Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca release in rats with post-myocardial infarction HF. We subjected male Wistar rats to left coronary artery ligation or sham operations.

Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction.

An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling.

Syndecan-4 Mice Have Smaller Muscle Fibers, Increased Akt/mTOR/S6K1 and Notch/HES-1 Pathways, and Alterations in Extracellular Matrix Components.

Background: Extracellular matrix (ECM) remodeling is essential for skeletal muscle development and adaption in response to environmental cues such as exercise and injury. The cell surface proteoglycan syndecan-4 has been reported to be essential for muscle differentiation, but few molecular mechanisms are known. Syndecan-4 mice are unable to regenerate damaged muscle, and display deficient satellite cell activation, proliferation, and differentiation.

NLRP3 Inflammasome Promotes Myocardial Remodeling During Diet-Induced Obesity.

Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1β and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations.

Accelerated magnetic resonance imaging tissue phase mapping of the rat myocardium using compressed sensing with iterative soft-thresholding.

Introduction: Tissue Phase Mapping (TPM) MRI can accurately measure regional myocardial velocities and strain. The lengthy data acquisition, however, renders TPM prone to errors due to variations in physiological parameters, and reduces data yield and experimental throughput. The purpose of the present study is to examine the quality of functional measures (velocity and strain) obtained by highly undersampled TPM data using compressed sensing reconstruction in infarcted and non-infarcted rat hearts.

The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload.

Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF.

The cardiac syndecan-4 interactome reveals a role for syndecan-4 in nuclear translocation of muscle LIM protein (MLP).

Costameres are signaling hubs at the sarcolemma and important contact points between the extracellular matrix and cell interior, sensing and transducing biomechanical signals into a cellular response. The transmembrane proteoglycan syndecan-4 localizes to these attachment points and has been shown to be important in the initial stages of cardiac remodeling, but its mechanistic function in the heart remains insufficiently understood. Here, we sought to map the cardiac interactome of syndecan-4 to better understand its function and downstream signaling mechanisms.

Coupling of the Na+/K+-ATPase to Ankyrin B controls Na+/Ca2+ exchanger activity in cardiomyocytes.

Aims: Ankyrin B (AnkB) is an adaptor protein that assembles Na+/K+-ATPase (NKA) and Na+/Ca2+ exchanger (NCX) in the AnkB macromolecular complex. Loss-of-function mutations in AnkB cause the AnkB syndrome in humans, characterized by ventricular arrhythmias and sudden cardiac death. It is unclear to what extent NKA binding to AnkB allows regulation of local Na+ and Ca2+ domains and hence NCX activity.

Hypokalemia-Induced Arrhythmias and Heart Failure: New Insights and Implications for Therapy.

Routine use of diuretics and neurohumoral activation make hypokalemia (serum K < 3. 5 mM) a prevalent electrolyte disorder among heart failure patients, contributing to the increased risk of ventricular arrhythmias and sudden cardiac death in heart failure. Recent experimental studies have suggested that hypokalemia-induced arrhythmias are initiated by the reduced activity of the Na/K-ATPase (NKA), subsequently leading to Ca overload, Ca/Calmodulin-dependent kinase II (CaMKII) activation, and development of afterdepolarizations.

Ryanodine receptor dispersion disrupts Ca release in failing cardiac myocytes.

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters.

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling.

Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation.

A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice.

Aims: Generation of reproducible cardiac disease phenotypes in mice is instrumental for investigating mechanisms leading to heart failure (HF). For decades, suture-based thoracic aortic constriction has been the preferred method for increasing left ventricular (LV) afterload in rodents, but the degree of stenosis resulting from this method is variable. In an effort to improve this methodology, we subjected mice to constriction of the ascending aorta using o-rings with fixed inner diameters (IDs).

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 [Ca]. 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.

Regional Dysfunction After Myocardial Infarction in Rats.

Background: Detailed understanding of regional function after myocardial infarction (MI) is currently incomplete. We aimed at investigating regional myocardial strain and work in post-MI rats with and without heart failure.

Methods And Results: Six weeks after induction of MI, 62 male Wistar-Hannover rats with a range of infarct sizes, plus 14 sham-operated rats, were examined by cine and phase-contrast magnetic resonance imaging.