Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level.

FKBP12.6, a binding protein to the immunosuppressant FK506, which also binds the ryanodine receptor (RyR2) in the heart, has been proposed to regulate RyR2 function and to have antiarrhythmic properties. However, the level of FKBP12.

Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca Handling and NRF2 Activation.

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.

Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.

Dysfunction of the sinoatrial node (SAN), the natural heart pacemaker, is common in heart failure (HF) patients. SAN spontaneous activity relies on various ion currents in the plasma membrane (voltage clock), but intracellular Ca2+ ([Ca2+]i) release via ryanodine receptor 2 (RYR2; Ca2+ clock) plays an important synergetic role. Whereas remodeling of voltage-clock components has been revealed in HF, less is known about possible alterations to the Ca2+ clock.

Ca mishandling in heart failure: Potential targets.

Ca mishandling is a common feature in several cardiovascular diseases such as heart failure (HF). In many cases, impairment of key players in intracellular Ca homeostasis has been identified as the underlying mechanism of cardiac dysfunction and cardiac arrhythmias associated with HF. In this review, we summarize primary novel findings related to Ca mishandling in HF progression.

Genetic Deletion of NOD1 Prevents Cardiac Ca Mishandling Induced by Experimental Chronic Kidney Disease.

Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response.

Innate Immune Receptors, Key Actors in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling.

BML-111 treatment prevents cardiac apoptosis and oxidative stress in a mouse model of autoimmune myocarditis.

Myocarditis is an inflammation of the myocardium that can progress to a more severe phenotype of dilated cardiomyopathy (DCM). Three main harmful factors determine this progression: inflammation, cell death, and oxidative stress. Lipoxins and their derivatives are endogenous proresolving mediators that induce the resolution of the inflammatory process.

Beneficial effects of paricalcitol on cardiac dysfunction and remodelling in a model of established heart failure.

Background And Purpose: The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca handling remodelling.

Experimental Approach: We used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF.

Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting.

The liver plays a key role during fasting to maintain energy homeostasis and euglycemia via metabolic processes mainly orchestrated by the insulin/glucagon ratio. We report here that fasting or calorie restriction protocols in C57BL6 mice promote a marked decrease in the hepatic protein levels of G protein-coupled receptor kinase 2 (GRK2), an important negative modulator of both G protein-coupled receptors (GPCRs) and insulin signaling. Such downregulation of GRK2 levels is liver-specific and can be rapidly reversed by refeeding.

Fibroblast growth factor-23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes.

Background: Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart.

Calcitriol, the Bioactive Metabolite of Vitamin D, Increases Ventricular K Currents in Isolated Mouse Cardiomyocytes.

Calcitriol, the bioactive metabolite of vitamin D, interacts with the ubiquitously expressed nuclear vitamin D receptor (VDR) to induce genomic effects, but it can also elicit rapid responses via membrane-associated VDR through mechanisms that are poorly understood. The down-regulation of K currents is the main origin of electrophysiological remodeling in pathological hypertrophy and heart failure (HF), which can contribute to action potential prolongation and subsequently increase the risk of triggered arrhythmias. Adult mouse ventricular myocytes were isolated and treated with 10 nM calcitriol or vehicle for 15-30 min.

Deficiency of NOD1 Improves the β-Adrenergic Modulation of Ca Handling in a Mouse Model of Heart Failure.

Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients.

Beneficial effects of leptin treatment in a setting of cardiac dysfunction induced by transverse aortic constriction in mouse.

Key Points: Leptin, is a 16 kDa pleiotropic peptide not only primarily secreted by adipocytes, but also produced by other tissues, including the heart. Controversy exists regarding the adverse and beneficial effects of leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca ] handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction. We find that leptin activates mechanisms that contribute to cardiac dysfunction under physiological conditions.

Role of NOD1 in Heart Failure Progression via Regulation of Ca Handling.

Background: Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases.

Calcitriol (1,25-dihydroxyvitamin D) increases L-type calcium current via protein kinase A signaling and modulates calcium cycling and contractility in isolated mouse ventricular myocytes.

Background: Calcitriol, the bioactive metabolite of vitamin D, exerts its effects through interaction with the nuclear vitamin D receptor (VDR) to induce genomic responses. Calcitriol may also induce rapid responses via plasma membrane-associated VDR, involving the activation of second messengers and modulation of voltage-dependent channels. VDR is expressed in cardiomyocytes, but the molecular and cellular mechanisms involved in the rapid responses of calcitriol in the heart are poorly understood.

NOD1 activation in cardiac fibroblasts induces myocardial fibrosis in a murine model of type 2 diabetes.

Cardiac fibrosis and chronic inflammation are common complications in type 2 diabetes mellitus (T2D). Since nucleotide oligomerization-binding domain 1 (NOD1), an innate immune receptor, is involved in the pathogenesis of insulin resistance and diabetes outcomes, we sought to investigate its involvement in cardiac fibrosis. Here, we show that selective staining of cardiac fibroblasts from T2D (db/db;db) mice exhibits up-regulation and activation of the NOD1 pathway, resulting in enhanced NF-κB and TGF-β signalling.