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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ca2+ plays a pivotal role in both excitation-contraction coupling (ECC) and activation of Ca2+-dependent signaling pathways. One of the remaining questions in cardiac biology is how Ca2+-dependent signaling pathways are regulated under conditions of continual Ca2+ transients that mediate cardiac contraction during each heartbeat. Ca2+-calmodulin-dependent protein kinase II (CaMKII) activation and its ability to regulate histone deacetylase 5 (HDAC5) nuclear shuttling represent a critical Ca2+-dependent signaling circuit for controlling cardiac hypertrophy and heart failure, yet the mechanism of activation by Ca2+ is not known. In this issue of the JCI, Wu et al. convincingly demonstrate that the inositol 1,4,5-trisphosphate receptor (InsP3R) is involved in local control of Ca2+ for activating CaMKII in the nuclear envelope of adult ventricular cardiac myocytes (see the related article beginning on page 675). The overall paradigm that is demonstrated is the best example of a molecular mechanism whereby signaling is directly regulated by a local Ca2+ pool that is disparate or geometrically insensitive to cytosolic Ca2+ underlying each contractile cycle.
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PMID:Dichotomy of Ca2+ in the heart: contraction versus intracellular signaling. 1651 2

More than 20 years have passed since the discovery that a collection of specific calcium/calmodulin-dependent phosphorylation events is the result of a single multifunctional kinase. Since that time, we have learned a great deal about this multifunctional and ubiquitous kinase, known today as calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII is interesting not only for its widespread distribution and broad specificity but also for its biophysical properties, most notably its activation by the critical second messenger complex calcium/calmodulin and its autophosphorylating capability. A central role for CaMKII has been identified in regulating a diverse array of fundamental cellular activities. Furthermore, altered CaMKII activity profoundly impacts function in the brain and heart. Recent findings that CaMKII expression in the heart changes during hypertrophy, heart failure, myocardial ischemia, and infarction suggest that CaMKII may be a viable therapeutic target for patients suffering from common forms of heart disease.
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PMID:A role for calcium/calmodulin-dependent protein kinase II in cardiac disease and arrhythmia. 1661 Mar 45

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.
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PMID:Roles of cardiac ryanodine receptor in heart failure and sudden cardiac death. 1670 9

Previous studies in transgenic mice and with isolated ryanodine receptors (RyR) have indicated that Ca2+-calmodulin-dependent protein kinase II (CaMKII) can phosphorylate RyR and activate local diastolic sarcoplasmic reticulum (SR) Ca2+ release events (Ca2+ sparks) and RyR channel opening. Here we use relatively controlled physiological conditions in saponin-permeabilized wild type (WT) and phospholamban knockout (PLB-KO) mouse ventricular myocytes to test whether exogenous preactivated CaMKII or endogenous CaMKII can enhance resting Ca2+ sparks. PLB-KO mice were used to preclude ancillary effects of CaMKII mediated by phospholamban phosphorylation. In both WT and PLB-KO myocytes, Ca2+ spark frequency was increased by both preactivated exogenous CaMKII and endogenous CaMKII. This effect was abolished by CaMKII inhibitor peptides. In contrast, protein kinase A catalytic subunit also enhanced Ca2+ spark frequency in WT, but had no effect in PLB-KO. Both endogenous and exogenous CaMKII increased SR Ca2+ content in WT (presumably via PLB phosphorylation), but not in PLB-KO. Exogenous calmodulin decreased Ca2+ spark frequency in both WT and PLB-KO (K0.5 approximately 100 nmol/L). Endogenous CaMKII (at 500 nmol/L [Ca2+]) phosphorylated RyR as completely in <4 minutes as the maximum achieved by preactivated exogenous CaMKII. After CaMKII activation Ca2+ sparks were longer in duration, and more frequent propagating SR Ca2+ release events were observed. We conclude that CaMKII-dependent phosphorylation of RyR by endogenous associated CaMKII (but not PKA-dependent phosphorylation) increases resting SR Ca2+ release or leak. Moreover, this may explain the enhanced SR diastolic Ca2+ leak and certain triggered arrhythmias seen in heart failure.
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PMID:Ca2+/Calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. 1691 97

The heart responds to injury and chronic pressure overload by pathologic growth and remodeling, which frequently result in heart failure and sudden death. Calcium-dependent signaling pathways promote cardiac growth and associated changes in gene expression in response to stress. The calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear factor of activated T cells (NFAT) transcription factors, serves as a transducer of calcium signals and is sufficient and necessary for pathologic cardiac hypertrophy and remodeling. Transient receptor potential (TRP) proteins regulate cation entry into cells in response to a variety of signals, and in skeletal muscle, expression of TRP cation channel, subfamily C, member 3 (TRPC3) is increased in response to neurostimulation and calcineurin signaling. Here we show that TRPC6 was upregulated in mouse hearts in response to activated calcineurin and pressure overload, as well as in failing human hearts. Two conserved NFAT consensus sites in the promoter of the TRPC6 gene conferred responsiveness to cardiac stress. Cardiac-specific overexpression of TRPC6 in transgenic mice resulted in heightened sensitivity to stress, a propensity for lethal cardiac growth and heart failure, and an increase in NFAT-dependent expression of beta-myosin heavy chain, a sensitive marker for pathologic hypertrophy. These findings implicate TRPC6 as a positive regulator of calcineurin-NFAT signaling and a key component of a calcium-dependent regulatory loop that drives pathologic cardiac remodeling.
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PMID:TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. 1709 78

In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na(+) channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIdelta(C) on Na(+) current (I(Na)) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIdelta(C) overexpression shifted voltage dependence of Na(+) channel availability by -6 mV (P < 0.05), and the shift was Ca(2+) dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIdelta(C) markedly increased persistent (late) inward I(Na) and intracellular Na(+) concentration (as measured by the Na(+) indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIdelta(C) overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na(+) channels. In vivo, transgenic CaMKIIdelta(C) overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na(+) channels. This alters I(Na) gating to reduce availability at high heart rate, while enhancing late I(Na) (which could prolong action potential duration). In mice, enhanced CaMKIIdelta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF.
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PMID:Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. 1712 32

Calcium (Ca(2+)) is the central second messenger in the translation of electrical signals into mechanical activity of the heart. This highly coordinated process, termed excitation-contraction coupling or ECC, is based on Ca(2+)-induced Ca(2+) release from the sarcoplasmic reticulum (SR). In recent years it has become increasingly clear that several Ca(2+)-dependent proteins contribute to the fine tuning of ECC. One of these is the Ca(2+)/calmodulin-dependent protein kinase (CaMK) of which CaMKII is the predominant cardiac isoform. During ECC CaMKII phosphorylates several Ca(2+) handling proteins with multiple functional consequences. CaMKII may also be co-localized to distinct target proteins. CaMKII expression as well as activity are reported to be increased in heart failure and CaMKII overexpression can exert distinct and novel effects on ECC in the heart and in isolated myocytes of animals. In the present review we summarize important aspects of the role of CaMKII in ECC with an emphasis on recent novel findings.
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PMID:Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. 1715 85

In response to pathologic stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is characterized by myocyte hypertrophy, myocyte death and fibrosis, resulting in impaired cardiac function and heart failure. Cardiac remodeling is associated with derepression of genes that contribute to disease progression. This review focuses on evidence linking members of the Ca(2+)/calmodulin-dependent protein kinase (CaMK) superfamily, specifically CaMKII, protein kinase D (PKD) and microtubule associated kinase (MARK), to stress-induced derepression of pathological cardiac gene expression through their effects on class IIa histone deacetylases (HDACs).
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PMID:Derepression of pathological cardiac genes by members of the CaM kinase superfamily. 1721 38

Ryanodine receptors (RyRs) function as intracellular Ca(2+) release channels on the endoplasmic and sarcoplasmic reticulum membranes. In striated muscles, Ca(2+) release through RyRs controls muscle excitation-contraction coupling. RyR channel function is regulated by a cytoplasmic scaffold domain that forms a macromolecular signaling complex including calstabin (formerly known as FK506-binding protein), calmodulin, phosphodiesterase, kinase and phosphatase proteins. An increasing number of genetic and acquired diseases has been associated with intracellular Ca(2+) leak. In heart failure, for instance, the RyR complex becomes altered, resulting in chronic channel dysfunction and chronic sarcoplasmic reticulum Ca(2+) leak. Recently, the efficacy of novel Ca(2+) release channel-stabilizing drugs has been demonstrated in cardiac and skeletal muscle disease models.
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PMID:Novel targets for treating heart and muscle disease: stabilizing ryanodine receptors and preventing intracellular calcium leak. 1730 22

Sustained myocardial hypertrophy is associated with an increased risk of sudden death and progression to heart failure. Multiple signal pathways are involved in cardiac hypertrophy and understanding their interaction may point to new therapeutic targets. In this work, we tested the hypothesis that adenovirus-mediated calmodulin (CaM) antisense expression will reduce the intracellular availability of CaM and inhibit the hypertrophic response. Three recombinant adenoviruses were constructed: AdASCaM, containing the AntiSense sequence of CaM and the enhanced green fluorescent protein (GFP) coding sequence; AdCaM, containing the coding sequence of CaM and the GFP sequence; and the AdGFP, containing the GFP coding sequence. Neonatal rat ventricular cardiomyocytes were infected with AdASCaM, AdCaM, or AdGFP and stimulated with phenylephrine (PE, 50 microM) or angiotensin II (AngII, 10 microM) for 48 h and cell surface area measured with planimetry. After PE treatment, the surface areas of cardiomyocytes infected with AdASCaM or AdGFP were 411 +/- 174.3 micro(2) and 832.6 +/- 372.3 micro(2), respectively (P < 0.01). After AngII treatment, the surface areas of cardiomyocytes infected with AdASCaM or AdGFP were 441.5 +/- 149.2 micro(2) and 726 +/- 328.3 micro(2), respectively (P < 0.01). Adenoviral expression of the CaM antisense (AdASCaM) significantly inhibited PE or AngII-induced cardiomyocyte hypertrophy. Cardiomyocytes infected with the AdCaM showed increased area when compared with those infected with the AdGFP. These results suggest that adenovirus-mediated changes in CaM expression may alter hypertrophy in cardiac myocytes.
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PMID:Adenoviral expression of calmodulin antisense reduces hypertrophy in cultured cardiomyocytes. 1743 95


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