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)

The K(v)4.2/4.3 channels are the primary subunits that contribute to the fast-inactivating, voltage-dependent transient outward K(+) current (I(to,fast)) in the heart. I(to,fast) is the critical determinant of the early repolarization of the cardiac action potential and plays an important role in the adaptive remodelling of cardiac myocytes, which usually causes cell volume changes, during myocardial ischaemia, hypertrophy and heart failure. It is not known, however, whether I(to,fast) is regulated by cell volume changes. In this study we investigated the molecular mechanism for cell volume regulation of I(to,fast) in native mouse left ventricular myocytes. Hyposmotic cell swelling caused a marked increase in densities of the peak I(to,fast) and a significant shortening in phase 1 repolarization of the action potential duration. The voltage-dependent gating properties of I(to,fast) were, however, not altered by changes in cell volume. In the presence of either protein kinase C (PKC) activator (12,13-dibutyrate) or phosphatase inhibitors (calyculin A and okadaic acid), hyposmotic cell swelling failed to further up-regulate I(to,fast). When expressed in NIH/3T3 cells, both K(v)4.2 and K(v)4.3 channels were also strongly regulated by cell volume in the same voltage-independent but PKC- and phosphatase-dependent manner as seen in I(to,fast) in the native cardiac myocytes. We conclude that K(v)4.2/4.3 channels in the heart are regulated by cell volume through a phosphorylation/dephosphorylation pathway mediated by PKC and serine/threonine phosphatase(s). These findings suggest a novel role of K(v)4.2/4.3 channels in the adaptive electrical and structural remodelling of cardiac myocytes in response to myocardial hypertrophy, ischaemia and reperfusion.
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PMID:Molecular mechanisms of regulation of fast-inactivating voltage-dependent transient outward K+ current in mouse heart by cell volume changes. 1608 89

Viral myocarditis can present as dramatic heart failure in the young, and chronic indolent cardiomyopathy in the older adult. The outcome of the disease is still poor, associated with high mortality during long-term follow-up. Enteroviral myocarditis serves as an excellent model to understand virus and host interactions. The virus enters the target cells via collaborating receptors, and this process triggers an inflammatory response in the host. The immune reaction is a two-edged sword, with appropriate activation of the immune system capable of clearing the virus, but excessive activation leads to a chronic inflammatory process that triggers the remodeling of the heart and consequent clinical heart failure. Through genetic dissection strategies, we have identified that the acquired immune system is activated through the T cell receptor and signaling amplification systems, such as the tyrosine kinase p56lck, phosphatase CD45 and downstream ERK1/2, and the family of cytokines. This signaling system not only promotes inflammatory cell clonal expansion but paradoxically also promotes viral proliferation. The innate immune system is now recognized as playing an ever-expanding role in coordinating the host immune response through the Toll-like receptors, triggering downstream signaling adaptors such as MyD88, IRAK, and TRIF/IRFs. These lead to activation of cytokines or interferons, depending on the balance of the signal contributions. The ongoing research in this area should help us to understand the immune response of the heart to viral infection, while identifying potential targets for therapy.
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PMID:Recent insights into the role of host innate and acquired immunity responses. 1632 61

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

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.
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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

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.
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PMID:Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. 1683 60

The natriuretic peptide receptor-A (NPR-A) mediates natriuretic, hypotensive, and antihypertrophic effects of natriuretic peptides through the production of cGMP. In pathological conditions such as heart failure, these effects are attenuated by homologous and heterologous desensitization mechanisms resulting in the dephosphorylation of the cytosolic portion of the receptor. In contrast with natriuretic peptide-induced desensitization, pressor hormone-induced desensitization is dependent on protein kinase C (PKC) stimulation and (or) cytosolic calcium elevation. Mechanisms by which PKC and Ca(2+) promote NPR-A desensitization are not known. The role of cGMP and of the cytosolic Ca(2+) pathways in NPR-A desensitization were therefore studied. In contrast with the activation of NPR-A by its agonist, activation of soluble guanylyl cyclases of LLC-PK1 cells by sodium nitroprusside also leads to a production of cGMP but without altering NPR-A activation. Consequently, cGMP elevation per se does not appear to mediate homologous desensitization of NPR-A. In addition, cytosolic calcium increase is required only for the heterologous desensitization pathway since the calcium chelator BAPTA-AM blocks only PMA or ionomycin-induced desensitization. Calcineurin inhibitors block the NPR-A guanylyl cyclase heterologous desensitization induced by ionomycin, suggesting an essential role for this Ca(2+)-stimulated phosphatase in NPR-A desensitization. In summary, the present report demonstrates that neither cGMP nor Ca(2+) cytosolic elevation cause NPR-A homologous desensitization. Our results also indicate for the first time a role for calcineurin in NPR-A heterologous desensitization.
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PMID:Role of cyclic GMP and calcineurin in homologous and heterologous desensitization of natriuretic peptide receptor-A. 1690 99

Increases in diastolic Ca2+ and impaired relaxation in failing hearts have been suggested to reflect the deteriorated function of the sarcoplasmic reticulum Ca-ATPase (SERCA2), whose activity is regulated by phospholamban (PLN). PLN is a reversible inhibitor of SERCA2's Ca2+ affinity and cardiac contractility. Studies in genetically altered mouse models have demonstrated that the levels and the degree of PLN phosphorylation are critical in modulating basal Ca2+ handling and contractility. Correspondingly, the depressed contractility in experimental and human heart failure is partially attributed to increased inhibition by PLN due to: (a) increases in PLN/SERCA2; and (b) decreases in PLN phosphorylation. The attenuated PLN phosphorylation is associated with increased type 1 phosphatase, which reflects dephosphorylation or inactivation of its inhibitor 1. Indeed PLN ablation was successful in rescuing cardiac remodelling and dysfunction in several heart failure mouse models, and inhibition of the phosphatase activity restored contractile parameters in failing rat hearts. Recently, two human PLN mutations, associated with either absence or sustained dephosphorylation of PLN, were linked to dilated cardiomyopathy. Thus, PLN modulation appears to be of paramount importance in humans, and further investigation into PLN function in higher mammalian species may provide insights into its potential as a therapeutic modality in heart failure.
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PMID:Phospholamban as a therapeutic modality in heart failure. 1701 11

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

Ca(2+) is a major intracellular messenger and nature has evolved multiple mechanisms to regulate free intracellular (Ca(2+))(i) level in situ. The Ca(2+) signal inducing contraction in cardiac muscle originates from two sources. Ca(2+) enters the cell through voltage dependent Ca(2+) channels. This Ca(2+) binds to and activates Ca(2+) release channels (ryanodine receptors) of the sarcoplasmic reticulum (SR) through a Ca(2+) induced Ca(2+) release (CICR) process. Entry of Ca(2+) with each contraction requires an equal amount of Ca(2+) extrusion within a single heartbeat to maintain Ca(2+) homeostasis and to ensure relaxation. Cardiac Ca(2+) extrusion mechanisms are mainly contributed by Na(+)/Ca(2+) exchanger and ATP dependent Ca(2+) pump (Ca(2+)-ATPase). These transport systems are important determinants of (Ca(2+))(i) level and cardiac contractility. Altered intracellular Ca(2+) handling importantly contributes to impaired contractility in heart failure. Chronic hyperactivity of the beta-adrenergic signaling pathway results in PKA-hyperphosphorylation of the cardiac RyR/intracellular Ca(2+) release channels. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the beta-adrenergic receptor, protein kinase C, Gq, and the down stream effectors such as mitogen activated protein kinases pathways, and the Ca(2+) regulated phosphatase calcineurin. A number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocytes. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underlie heart diseases. Recent progress in molecular cardiology makes it possible to envision a new therapeutic approach to heart failure (HF), targeting key molecules involved in intracellular Ca(2+) handling such as RyR, SERCA2a, and PLN. Controlling these molecular functions by different agents have been found to be beneficial in some experimental conditions.
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PMID:Calcium signaling phenomena in heart diseases: a perspective. 1711 49

The molecular basis of the beneficial effects associated with exercise training (ET) on overall ventricular function (VF) in heart failure (HF) remains unclear. We investigated potential Ca(2+) handling abnormalities and whether ET would improve VF of mice lacking alpha(2A)- and alpha(2C)-adrenoceptors (alpha(2A)/alpha(2C)ARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)ARKO mice in a C57BL/J genetic background (5-7 mo of age) was randomly assigned into untrained and trained groups. VF was assessed by two-dimensional guided M-mode echocardiography. Cardiac myocyte width and ventricular fibrosis were evaluated with a computer-assisted morphometric system. Sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), phospholamban (PLN), phospho-Ser(16)-PLN, phospho-Thr(17)-PLN, phosphatase 1 (PP1), and Na(+)-Ca(2+) exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. alpha(2A)/alpha(2C)ARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in alpha(2A)/alpha(2C)ARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in alpha(2A)/alpha(2C)ARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser(16)-PLN (63%), phospho-Thr(17)-PLN (211%) in alpha(2A)/alpha(2C)ARKO mice. Furthermore, ET restored NCX and PP1 expression in alpha(2A)/alpha(2C)ARKO to untrained WT mice levels. Thus, we provide evidence that Ca(2+) handling is impaired in this HF model and that overall VF improved upon ET, which was associated to changes in the net balance of cardiac Ca(2+) handling proteins.
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PMID:Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure. 1724 91


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