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

Ca2+/calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIdelta, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIdelta deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP3R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca2+ spark frequency only in WT mice. We suggest that CaMKIIdelta contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKIIdelta activation can limit the progression to heart failure.
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PMID:Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. 1942 97

Phosphorylation of the cardiac ryanodine receptor (RyR2) is a key mechanism regulating sarcoplasmic reticulum (SR) Ca2+ release. Differences in opinion have arisen over the importance assigned to specific phosphorylation sites on RyR2, over the kinase (s) suggested to directly phosphorylate RyR2 and surrounding the possibility that altered phosphorylation of RyR2 is associated with contractile dysfunction observed in heart failure. Ca2+/calmodulin dependent protein kinase II (CaMKII) can phosphorylate RyR2 and modulate its activity. This phosphorylation positively modulates cardiac inotropic function but in extreme situations such as heart failure, elevated CaMKII activity can adversely increase Ca2+ release from the SR and lead to arrhythmogenesis. Although other kinases can phosphorylate RyR2, most notably cAMP-dependent protein kinase (PKA), evidence for a key role of CaMKII in mediating RyR2-dependent Ca2+ release is emerging. Future challenges include (i) fully identifying mechanisms of CaMKII interaction with the RyR2 complex and (ii) given the ubiquitous expression of CaMKII, developing selective strategies to modulate RyR2-targeted CaMKII activity and allow improved understanding of its role in normal and diseased heart.
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PMID:Cardiac ryanodine receptor phosphorylation by CaM Kinase II: keeping the balance right. 1948 9

Sarcalumenin (SAR), a Ca(2+)-binding protein located in the longitudinal sarcoplasmic reticulum (SR), regulates Ca(2+) reuptake into the SR by interacting with cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a). We have previously demonstrated that SAR deficiency induced progressive heart failure in response to pressure overload, despite mild cardiac dysfunction in sham-operated SAR knockout (SARKO) mice (26). Since responses to physiological stresses often differ from those to pathological stresses, we examined the effects of endurance exercise on cardiac function in SARKO mice. Wild-type (WT) and SARKO mice were subjected to endurance treadmill exercise training ( approximately 65% of maximal exercise ability for 60 min/day) for 12 wk. After exercise training, maximal exercise ability was significantly increased by 5% in WT mice (n = 6), whereas it was significantly decreased by 37% in SARKO mice (n = 5). Cardiac function assessed by echocardiographic examination was significantly decreased in accordance with upregulation of biomarkers of cardiac stress in SARKO mice after training. After training, expression levels of SERCA2a protein were significantly downregulated by 30% in SARKO hearts, whereas they were significantly upregulated by 59% in WT hearts. Consequently, SERCA2 activity was significantly decreased in SARKO hearts after training. Furthermore, the expression levels of other Ca(2+)-handling proteins, including phospholamban, ryanodine receptor 2, calsequestrin 2, and sodium/calcium exchanger 1, were significantly decreased in SARKO hearts after training. These results indicate that SAR plays a critical role in maintaining cardiac function under physiological stresses, such as endurance exercise, by regulating Ca(2+) transport activity into the SR. SAR may be a primary target for exercise-related adaptation of the Ca(2+) storage system in the SR to preserve cardiac function.
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PMID:Sarcalumenin is essential for maintaining cardiac function during endurance exercise training. 1950 53

The cardiac action potential is primarily shaped by the orchestrated function of several different types of ion channels and transporters. One of the regional differences believed to play a major role in the progression and stability of the action potential is the transmural gradient of electrical activity across the ventricular wall. An altered balance in the ionic currents across the free wall is assumed to be a substrate for arrhythmia. A large fraction of patients with heart failure experience ventricular arrhythmia. However, the underlying substrate of these functional changes is not well-established as expression analyses of human heart failure (HF) are sparse. We have investigated steady-state RNA levels by quantitative polymerase chain reaction of ion channels, transporters, connexin 43, and miR-1 in 11 end-stage HF and seven nonfailing (NF) hearts. The quantifications were performed on endo-, mid-, and epicardium of left ventricle, enabling us to establish changes in the transmural expression gradient. Transcripts encoding Cav1.2, HCN2, Kir2.1, KCNE1, SUR1, and NCX1 were upregulated in HF compared to NF while a downregulation was observed for KChIP2, SERCA2, and miR-1. Additionally, the transmural gradient of KCNE1, KChIP2, Kir6.2, SUR1, Nav1.5, NCX1, and RyR2 found in NF was only preserved for KChiP2 and Nav1.5 in HF. The transmural gradients of NCX1, Nav1.5, and KChIP2 and the downregulation of KChIP2 were confirmed by Western blotting. In conclusion, our results reveal altered expression of several cardiac ion channels and transporters which may in part explain the increased susceptibility to arrhythmia in end-state failing hearts.
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PMID:Transmural expression of ion channels and transporters in human nondiseased and end-stage failing hearts. 1976 67

In the 8 years since the discovery of the genetic bases of catecholaminergic polymorphic ventricular tachycardia (CPVT), we have witnessed a remarkable improvement of knowledge on arrhythmogenic mechanisms involving disruption of cardiac Ca(2+) homeostasis. Studies on the consequences of RyR2 and CASQ2 mutations in cellular systems and mouse models have shed new light on pathways that are also implicated in arrhythmias occurring in highly prevalent diseases, such as heart failure. This research track has also led to the identification of therapeutic targets of potential clinical impact to abate the burden of sudden death in CPVT. Here, we review the current knowledge on the pathophysiology of CPVT also highlighting the existing controversies and possible future development.
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PMID:Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. 1987 46

intracellular Ca(2+) handling by the sarcoplasmic reticulum (SR) plays a crucial role in the pathogenesis of heart failure (HF). Despite extensive effort, the underlying causes of abnormal SR Ca(2+) handling in HF have not been clarified. To determine whether the diastolic SR Ca(2+) leak along with reduced Ca(2+) reuptake is required for decreased contractility, we investigated the cytosolic Ca(2+) transients and SR Ca(2+) content and assessed the expression of ryanodine receptor (RyR2), FK506 binding protein (FKBP12.6), SR-Ca(2+) ATPase (SERCA2a), and L-type Ca(2+) channel (LTCC) using an SD-rat model of chronic HF. We found that the cytosolic Ca(2+) transients were markedly reduced in amplitude in HF myocytes (DeltaF/F(0) = 12.3 +/- 0.8) compared with control myocytes (DeltaF/F(0) = 17.7 +/- 1.2, P < 0.01), changes paralleled by a significant reduction in the SR Ca(2+) content (HF: DeltaF/F(0) = 12.4 +/- 1.1, control: DeltaF/F(0) = 32.4 +/- 1.9, P < 0.01). Moreover, we demonstrated that the expression of FKBP12.6 associated with RyR2, SERCA2a, and LTCC was significantly reduced in rat HF. These results provide evidence for phosphorylation-induced detachment of FKBP12.6 from RyRs and down-regulation of SERCA2a and LTCC in HF. We conclude that diastolic SR Ca(2+) leak (due to dissociation of FKBP12.6 from RyR2) along with reduced SR Ca(2+) uptake (due to down-regulation of SERCA2a) and defective E-C coupling (due to down-regulation of LTCC) could contribute to HF.
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PMID:Altered intracellular Ca2+ regulation in chronic rat heart failure. 1999 92

Recent evidence shows that the auxiliary subunit KChIP2, which assembles with pore-forming Kv4-subunits, represents a new potential regulator of the cardiac calcium-independent transient outward potassium current (I(to)) density. In hypertrophy and heart failure, KChIP2 expression has been found to be significantly decreased. Our aim was to examine the role of KChIP2 in cardiac hypertrophy and the effect of restoring its expression on electrical remodeling and cardiac mechanical function using a combination of molecular, biochemical and gene targeting approaches. KChIP2 overexpression through gene transfer of Ad.KChIP2 in neonatal cardiomyocytes resulted in a significant increase in I(to)-channel forming Kv4.2 and Kv4.3 protein levels. In vivo gene transfer of KChIP2 in aortic banded adult rats showed that, compared to sham-operated or Ad.beta-gal-transduced hearts, KChIP2 significantly attenuated the developed left ventricular hypertrophy, robustly increased I(to) densities, shortened action potential duration, and significantly altered myocyte mechanics by shortening contraction amplitudes and maximal rates of contraction and relaxation velocities and decreasing Ca(2+) transients. Interestingly, blocking I(to) with 4-aminopyridine in KChIP2-overexpressing adult cardiomyocytes significantly increased the Ca(2+) transients to control levels. One-day-old rat pups intracardially transduced with KChIP2 for two months then subjected to aortic banding for 6-8 weeks (to induce hypertrophy) showed similar echocardiographic, electrical and mechanical remodeling parameters. In addition, in cultured adult cardiomyocytes, KChIP2 overexpression increased the expression of Ca(2+)-ATPase (SERCA2a) and sodium calcium exchanger but had no effect on ryanodine receptor 2 or phospholamban expression. In neonatal myocytes, KChIP2 notably reversed Ang II-induced hypertrophic changes in protein synthesis and MAP-kinase activation. It also significantly decreased calcineurin expression, NFATc1 expression and nuclear translocation and its downstream target, MCiP1.4. Altogether, these data show that KChIP2 can attenuate cardiac hypertrophy possibly through modulation of intracellular calcium concentration and calcineurin/NFAT pathway.
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PMID:KChIP2 attenuates cardiac hypertrophy through regulation of Ito and intracellular calcium signaling. 2005 Dec 48

Ryanodine receptors (RyRs) are high conductance intracellular cation channels that release calcium ions from stores such as the endoplasmic reticulum and sarcoplasmic reticulum. Although RyRs are expressed in many cell types, their roles have only been extensively characterised in tissues in which they are abundant: RyR1 is essential for excitation-contraction coupling in skeletal muscle; whereas RyR2 is required for the analogous signal transduction pathway in heart. Defects in RyR1 cause malignant hyperthermia and a spectrum of myopathies in skeletal muscle; whereas RyR2 dysregulation can result in fatal cardiac arrhythmias and is involved in heart failure. Altered RyR gating has been implicated in a range of other diseases, including epilepsy, neurodegeneration, pain and cancer. RyRs interact with a range of toxic substances, providing insights into their functional and structural properties. Consequently, these channel complexes represent potential therapeutic targets for treatment of numerous diseases. Furthermore, strategies for combating multicellular parasites and agricultural pests could exploit pharmacological differences between their RyRs and those of vertebrates. However, available pharmacological tools for manipulation of RyR gating are generally unsuitable for clinical, veterinary or agricultural use, owing to their lack of selectivity, inappropriate solubility in the aqueous or lipid environment, or generation of side-effects. The expression, subcellular distribution and gating of RyRs is modified by a wide variety of cellular proteins, some of which are expressed in a developmentally or tissue-restricted manner. This commentary examines the possibility of manipulating the expression and function of such proteins in order develop new drugs acting on RyR channel complexes.
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PMID:Ryanodine receptor calcium channels and their partners as drug targets. 2009 79

The mechanisms responsible for sudden cardiac death in heart failure (HF) are unclear. We investigated early and delayed afterdepolarizations (EADs, DADs) in HF. Cardiomyocytes were enzymatically isolated from the right ventricle (RV) and the septum of rats 8 weeks after myocardial infarction (MI) and sham-operated animals. Membrane capacitance, action potentials (AP) and ionic currents were measured by whole-cell patch-clamp. The [Ca(2+)](i) transients and Ca(2+) sparks were recorded with Fluo-4 during fluorescence measurements. Arrhythmia was triggered in 40% of MI cells (not in sham) using trains of 5 stimulations at 2.0 Hz. EADs and DADs occurred in distinct cell populations both in the RV and the septum. EADs occurred in normal-sized PMI cells (<230 pF), whereas DADs occurred in hypertrophic PMI cells (>230 pF). All cells exhibited prolonged APs due to reduced I(to) current. However, additional modifications in Ca(2+)-dependent ionic currents occurred in hypertrophic cells: a decrease in the inward rectifier K(+) current I(K1), and a slowing of L-type Ca(2+) current inactivation which was responsible for the lack of adaptation of APs to abrupt changes in the pacing rate. The occurrence of spontaneous Ca(2+) sparks, reflecting ryanodine receptor (RyR2) diastolic activity, increased with hypertrophy. The [Ca(2+)](i) transient amplitude, sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) sparks amplitude were all inversely correlated with cell size. We conclude that the trophic status of cardiomyocytes determines the type of cellular arrhythmia in MI rats, based on differential electrophysiological remodeling which may reflect early-mild and late-severe or differential modifications in the RyR2 function.
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PMID:Cardiomyocytes hypertrophic status after myocardial infarction determines distinct types of arrhythmia: role of the ryanodine receptor. 2010 82

In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although intracellular calcium (Ca(2+)) has a central role in hypertrophic signaling pathways, the Ca(2+) source for activating these pathways remains elusive. We hypothesized that pathological sarcoplasmic reticulum Ca(2+) leak through defective cardiac intracellular Ca(2+) release channels/ryanodine receptors (RyR2) accelerates heart failure development by stimulating Ca(2+)-dependent hypertrophic signaling. Mice heterozygous for the gain-of-function mutation R176Q/+ in RyR2 and wild-type mice were subjected to transverse aortic constriction. Cardiac function was significantly lower, and cardiac dimensions were larger at 8 weeks after transverse aortic constriction in R176Q/+ compared with wild-type mice. R176Q/+ mice displayed an enhanced hypertrophic response compared with wild-type mice as assessed by heart weight:body weight ratios and cardiomyocyte cross-sectional areas after transverse aortic constriction. Quantitative PCR revealed increased transcriptional activation of cardiac stress genes in R176Q/+ mice after transverse aortic constriction. Moreover, pressure overload resulted in an increased sarcoplasmic reticulum Ca(2+) leak, associated with higher expression levels of the exon 4 splice form of regulator of calcineurin 1, and a decrease in nuclear factor of activated T-cells phosphorylation in R176Q/+ mice compared with wild-type mice. Taken together, our results suggest that RyR2-dependent sarcoplasmic reticulum Ca(2+) leak activates the prohypertrophic calcineurin/nuclear factor of activated T-cells pathway under conditions of pressure overload.
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PMID:Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model. 2015 50


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