Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A study by Xiao and co-workers in this issue of the Biochemical Journal demonstrates PKA (protein kinase A)-dependent phosphorylation of Ser-2030 on the cardiac ryanodine receptor (RyR2) that is activated by beta-adrenergic agonists. They show that RyR2 phosphorylation at this site is not appreciably altered in heart failure samples, but retains PKA-dependence of phosphorylation. They contrast this with RyR2 phosphorylation at Ser-2808, a site previously reported to be the key and only PKA target site on RyR2. Here Ser-2808 phosphorylation was found to be relatively insensitive to either PKA activation or inhibition. These results add important new information to a highly controversial field. This issue is important because it is increasingly clear that altered regulation of the gating of the RyR2 sarcoplasmic reticulum Ca2+-release channel (e.g. by phosphorylation) is critically important in mediating altered diastolic sarcoplasmic reticulum Ca2+ release. This may contribute to both reduced cardiac function and arrhythmogenesis in humans carrying mutations in the RyR2 gene and with acquired heart failure of varied aetiology. This study brings some new answers, but also raises additional new questions that will require further investigation.
 ...
PMID:Cardiac ryanodine receptor phosphorylation: target sites and functional consequences. 1648 56

Calcium (Ca2+) plays an important role as a messenger in the excitation-contraction coupling process of the myocardium. It is stored in the sarcoplasmic reticulum (SR) and released via a calcium release channel called the ryanodine receptor. Cardiac ryanodine receptor (RyR2) controls Ca2+ release, which is essential for cardiac contractility. There are several molecules which bind and regulate the function of RyR2 including calstabin2, calmodulin, protein kinase A (PKA), phosphatase, sorcin and calsequestrin. Alteration of RyR2 and associated molecules can cause functional and/or structural changes of the heart, leading to heart failure and sudden cardiac death. In this review, the alteration of RyR2 and its regulatory proteins, and its roles in heart failure and sudden cardiac death, are discussed. Evidence of a possible novel therapy targeting RyR2 and its associated regulatory proteins, currently proposed by investigators, is also included in this article.
 ...
PMID:Roles of cardiac ryanodine receptor in heart failure and sudden cardiac death. 1670 9

It is suggested that protein kinase A (PKA)-dependent phosphorylation of cardiac ryanodine receptors (RyR2) is linked to the development of heart failure and the generation of fatal cardiac arrhythmias. It is also suggested that RyR2 is phosphorylated to 75% of maximum levels in heart failure resulting in leaky, unregulated channels gating in subconductance states. We now demonstrate that this is unlikely, as RyR2 isolated from nonfailing cardiac muscle is phosphorylated to 75% of maximum at serine-2809, and in this situation, RyR2 displays low open probability (P(o)) (0.059+/-0.010 [SEM]; n=30) and normal regulation of gating by Ca(2+) and other ligands. However, when serine-2809 is PKA phosphorylated to maximum levels on RyR2, unique changes in channel behavior are observed. The channel displays enhanced single-channel conductance, very long open states causing large increases in P(o), and no evidence of subconductance states. Dephosphorylation of channels by protein phosphatase 1 (from 75% to near 0% at serine-2809) also enhances RyR2 channel activity through abbreviation of closed lifetimes. We propose that channels phosphorylated to 75% of maximum at serine-2809 occupy a natural low point in the RyR2 activity landscape. This optimizes channel control, which can be accomplished either by enhanced or decreased phosphorylation, making the channel particularly sensitive to the kinase:phosphatase balance. Pathological situations such as heart failure might upset this balance and thereby permit prolonged stoichiometric phosphorylation of serine-2809, which would be required for dysregulation of SR Ca(2+) release.
 ...
PMID:Maximum phosphorylation of the cardiac ryanodine receptor at serine-2809 by protein kinase a produces unique modifications to channel gating and conductance not observed at lower levels of phosphorylation. 1670 1

The depressed sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and Ca2+-release channels (ryanodine receptor RyR2) are involved in the diabetic cardiomyopathy. However, an implication of a down-regulation of FK506-binding protein or calstabin-2 (FKBP12.6) is undefined. It was hypothesized that the down-regulation of FKBP12.6 and SERCA2a of the intracellular calcium handling system is closely related to an up-regulated endothelin (ET) system. An ET receptor antagonist CPU0213 is newly discovered and expected to ameliorate cardiac insufficiency which is mediated by the depressed FKBP12.6 and SERCA2a in diabetic rat heart. Diabetes was developed in male Sprague-Dawley rats 8 weeks after an injection of streptozotocin (60 mg/kg IP), and CPU0213 was instituted 30 mg/kg, SC in the last 4 weeks. The assessment of the cardiac function, cardiac calcium handling proteins, endothelin system, and redox enzyme system were conducted. The compromised cardiac function in diabetic rats was accompanied by a significant down-regulation of expression of FKBP12.6 as well as SERCA2a and phospholamban. These were closely linked with an increased ET-1 and up-regulation of endothelin converting enzyme, PropreET1, and inducible nitric oxide synthase mRNA in diabetic cardiomyopathy. After 4-week treatment, CPU0213 was capable to attenuate completely the down-regulated FKBP12.6 and SERCA2a, and up-regulated ET system in association with a recovery of the cardiac insufficiency of diabetic cardiomyopathy.
 ...
PMID:A novel endothelin receptor antagonist CPU0213 improves diabetic cardiac insufficiency attributed to up-regulation of the expression of FKBP12.6, SERCA2a, and PLB in rats. 1681 72

This review focuses on role played by two modulators of ryanodine receptors (RyRs), one a small molecule (1,4-benzothiazepine) and the other a protein subunit of the channel (FKBP or calstabin), both of which exert potent effects on the channel. These regulators of the RyR channels have potential therapeutic implications in that the small molecule and the protein have novel anti-arrhythmic and anti-heart failure activities involving the cardiac (RyR2) and skeletal (RyR1) ryanodine receptors. Protein kinase A (PKA) hyperphosphorylation of RyR2 in failing hearts or mutations in RyR2 linked to sudden cardiac death (SCD) can result in diastolic sarcoplasmic reticulum (SR) Ca2+ leak that can trigger fatal cardiac arrhythmias, and deplete SR Ca2+ stores contributing to decreased contractility. We and others have identified a class of small molecules derived from 1,4-benzothiazepines, that enhance the binding affinity of calstabin 2 for RyR2 and reduce the diastolic SR Ca2+ leak, even when the channel is PKA hyperphosphorylated. Therefore, this class of compounds has tremendous potential as novel therapeutics for heart failure and cardiac arrhythmias.
 ...
PMID:Novel therapy for heart failure and exercise-induced ventricular tachycardia based on 'fixing' the leak in ryanodine receptors. 1701 10

The RyR (ryanodine receptor) mediates rapid Ca2+ efflux from the ER (endoplasmic reticulum) and is responsible for triggering numerous Ca2+-activated physiological processes. The most studied RyR-mediated process is excitation-contraction coupling in striated muscle, where plasma membrane excitation is transmitted to the cell interior and results in Ca2+ efflux that triggers myocyte contraction. Recently, single-residue mutations in the cardiac RyR (RyR2) have been identified in families that exhibit CPVT (catecholaminergic polymorphic ventricular tachycardia), a condition in which physical or emotional stress can trigger severe tachyarrhythmias that can lead to sudden cardiac death. The RyR2 mutations in CPVT are clustered in the N- and C-terminal domains, as well as in a central domain. Further, a critical signalling role for dysfunctional RyR2 has also been implicated in the generation of arrhythmias in the common condition of HF (heart failure). We have prepared cardiac RyR2 plasmids with various CPVT mutations to enable expression and analysis of Ca2+ release mediated by the wild-type and mutated RyR2. These studies suggest that the mutational locus may be important in the mechanism of Ca2+ channel dysfunction. Understanding the causes of aberrant Ca2+ release via RyR2 may assist in the development of effective treatments for the ventricular arrhythmias that often leads to sudden death in HF and in CPVT.
 ...
PMID:Role of ryanodine receptor mutations in cardiac pathology: more questions than answers? 1705 26

Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca(2+). A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca(2+) pump and the ryanodine receptor 2, leading to increased Ca(2+) uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca(2+)-release channels and accelerates Ca(2+) reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca(2+) transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca(2+) cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure.
 ...
PMID:Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. 1713 43

A hyperadrenergic state is a seminal aspect of chronic heart failure. Also, "Takotsubo stress cardiomyopathy," is associated with increased plasma catecholamine levels. The mechanisms of myocyte damage secondary to excess catecholamine exposure as well as the consequence of this neurohumoral burst on cardiac stem cells (CSCs) are unknown. Cardiomyocytes and CSCs were exposed to high doses of isoproterenol (ISO), in vivo and in vitro. Male Wistar rats received a single injection of ISO (5 mg kg-1) and were sacrificed 1, 3, and 6 days later. In comparison with controls, LV function was impaired in rats 1 day after ISO and started to improve at 3 days. The fraction of dead myocytes peaked 1 day after ISO and decreased thereafter. ISO administration resulted in significant ryanodine receptor 2 (RyR2) hyperphosphorylation and RyR2-calstabin dissociation. JTV519, a RyR2 stabilizer, prevented the ISO-induced death of adult myocytes in vitro. In contrast, CSCs were resistant to the acute neurohumoral overload. Indeed, CSCs expressed a decreased and inverted complement of beta1/beta2-adrenoreceptors and absence of RyR2, which may explain their survival to ISO insult. Thus, a single injection of ISO causes diffuse myocyte death through Ca2+ leakage secondary to the acutely dysfunctional RyR2. CSCs are resistant to the noxious effects of an acute hyperadrenergic state and through their activation participate in the response to the ISO-induced myocardial injury. The latter could contribute to the ability of the myocardium to rapidly recover from acute hyperadrenergic damage.
 ...
PMID:Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. 1723 29

Both beta-adrenergic blockade and bradycardia may contribute to the therapeutic effect of beta-blockers in chronic heart failure (CHF). This study tested the relative importance of bradycardia by comparing cilobradine (Cilo), a sinus node inhibitor, with a beta-blocker, metoprolol (Meto), in an established canine model of CHF. Dogs were chronically instrumented for hemodynamic and left ventricular (LV) volume measurements. CHF was created by daily coronary embolization via a chronically implanted coronary (left anterior descending coronary artery) catheter. After establishment of CHF, control (n=6), Meto (30 mg/day, n=5), Cilo (low) (1 mg/kg/day, n=5), or Cilo (high) (3 mg/kg/day, n=5) was given orally for 12 weeks. Systemic hemodynamics, echocardiography, and pressure volume analysis were measured at baseline, at CHF, and 3 months after treatment in an awake state. Protein levels of cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), ryanodine receptor (RyR2), and Na+-Ca2+ exchanger (NCX1) were measured by Western blot. RyR2 protein kinase A (PKA) phosphorylation was determined by back-phosphorylation. After 12 weeks, Meto and Cilo (high and low) produced similar bradycardic effects, accompanied by a significantly improved LV dP/dt versus control [Meto, 2602+/-70; Cilo (low), 2517+/-45; Cilo (high), 2579+/-78; control, 1922+/-115 mm Hg/s; p<0.05]. Both Meto and Cilo (high) normalized protein levels of SERCA2a and NCX1 and reversed PKA hyperphosphorylation of RyR2, in contrast to controls. High-dose cilobradine effectively produced bradycardia and improved cardiac function after CHF, comparable with metoprolol. Restored protein levels of SERCA2a and improved function of RyR2 may be important mechanisms associated with cilobradine therapy.
 ...
PMID:Bradycardic therapy improves left ventricular function and remodeling in dogs with coronary embolization-induced chronic heart failure. 1727 96

Heart failure (HF) is a major and growing public health problem in the world. About 50% of deaths in HF occur suddenly due to malignant arrhythmia. Therefore, exploring the further mechanisms of chronic HF and finding new therapy targets are essential for the progression of HF treatment. Recently, some published papers suggested that myocardial neural remodeling and abnormal excitation-contraction (EC) coupling might partly contribute to the development of HF and sudden cardiac death. Even though a few studies have demonstrated that the sympathetic nerve system (SNS) may have significant impact on the functional states of myocardial EC coupling through the beta-adrenergic signaling pathway, so far, it still remains unknown that whether neural remodeling affects the EC coupling. Studies from Marks' group demonstrated that 70% of cardiac ryanodine receptors (RyR2), which located on the sarcoplasmic reculum (SR) controlling intracellular Ca(2+) release and muscle contraction in the heart, from failing hearts were abnormal and only 15% exhibited the most severe defects. In addition, Litwin et al. observed that temporal and spatial heterogeneities in local Ca(2+) release events in a rabbit model of HF after myocardial infarction. Because some studies have demonstrated that chronic SNS hyperactivity in HF led to protein kinase A (PKA) hyperphosphorylation of RyR2 in the heart, and the myocardial sympathetic nerve distribution become heterogeneous in the setting of HF. Thus, it is reasonable for us to propose the hypothesis that neural remodeling may partly account for the abnormality of EC coupling in HF.
 ...
PMID:Neural remodeling may partly contribute to the abnormality of excitation-contraction coupling in heart failure. 1756 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>