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 26S proteasome is a multicatalytic threonine protease complex responsible for degradation of the majority of proteins in eukaryotic cells. In the last two decades, the ubiquitin proteasome system (UPS) has been increasingly recognized as an integral component in numerous biologic processes including cell proliferation, adaptation to stress, and cell death. The turnover of intracellular proteins inevitably affects the contributions of these molecules to cellular networks and pathways in any given tissue or organ, including the myocardium. Perturbations in the protein-degradation process have been shown to affect protein turnover and thereby affect the cardiac cell functions that these molecules are designated to carry out, engendering diseased cardiac phenotypes. Recent studies have implicated the role of proteasomes in stressed cardiac phenotypes including postischemia-reperfusion injury and cardiac remodeling (e.g., heart failure). The 26S proteasomes also appear to be susceptible to modulation by stresses (e.g., reactive oxygen species). This review focuses on roles of the 26S proteasome system in protein degradation; it provides an overview of the progress made in cardiac proteasome research as well as a discussion of recent controversies regarding the UPS system in diseased cardiac phenotypes.
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PMID:Protein degradation by the 26S proteasome system in the normal and stressed myocardium. 1698 21

Human and experimental heart failure is characterized by increases in type-1 protein phosphatase activity, which may be partially attributed to inactivation of its endogenous regulator, protein phosphatase inhibitor-1. Inhibitor-1 represents a nodal integrator of two major second messenger pathways, adenosine 3',5'-cyclic monophosphate (cAMP) and calcium, which mediate its phosphorylation at threonine 35 and serine 67, respectively. Here, using recombinant inhibitor-1 wild-type and mutated proteins, we identified a novel phosphorylation site in inhibitor-1, threonine 75. This phosphoamino acid was phosphorylated in vitro by protein kinase Calpha independently and to the same extent as serine 67, the previous protein kinase Calpha-identified site. Generation of specific antibodies for the phosphorylated and dephosphorylated threonine 75 revealed that this site is phosphorylated in rat and dog hearts. Adenoviral-mediated expression of the constitutively phosphorylated threonine 75 inhibitor-1 in isolated myocytes was associated with specific stimulation of type-1 protein phosphatase activity and marked inhibition of the sarcoplasmic calcium pump affinity for calcium, resulting in depressed contractility. Thus, phosphorylation of inhibitor-1 at threonine 75 represents a new mechanism of cardiac contractility regulation, partially through the alteration of sarcoplasmic reticulum calcium transport activity.
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PMID:Identification of a novel phosphorylation site in protein phosphatase inhibitor-1 as a negative regulator of cardiac function. 1704 26

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

To test the hypothesis that AMP-activated protein kinase (AMPK) is possibly the downstream signaling molecule of certain subtypes of adrenergic receptor (AR) in the heart, we evaluated AMPK activation mediated by ARs in H9C2 cells, a rat cardiac source cell line, and rat hearts. The AMPK-alpha subunit and the phosphorylation level of Thr(172)-AMPK-alpha subunit were subjected to Western blot analysis. Osmotic minipumps filled with norepinephrine (NE), phenylephrine (PE) or vehicle [0.01% (W/V) vitamin C solution] were implanted into male Sprague-Dawley rats subcutaneously. The pumps delivered NE or PE continuously at the rate of 0.2 mg/kg per hour. After 7-day infusion, the activity of AMPK was examined following immunoprecipitation with anti-AMPK-alpha antibody. At the cellular level, we found that NE elevated AMPK phosphorylation level in a dose- and time-dependent manner, with the maximal effect at 10 micromol/L NE after 10-minute treatment. This effect was insensitive to propranolol, a specific beta-AR antagonist, but abolished by prazosin, an alpha(1)-AR antagonist, suggesting that alpha(1)-AR but not beta-AR mediated the phosphorylation of AMPK. Moreover, the results from rat models of 7-day-infusion of AR agonists demonstrated that the activity of AMPK was significantly higher in NE (7.4-fold) and PE (6.0-fold) infusion groups than that in the vehicle group (P<0.05, n=6). On the other hand, no obvious cardiac hypertrophy and tissue fibrosis changes were observed in PE-infused rats. Taken together, our results demonstrate that alpha(1)-AR stimulation enhances the activity of AMPK, indicating an important role of alpha(1)-AR stimulation in the regulation of AMPK in the heart. Understanding the activation of AMPK mediated by alpha(1)-AR might have clinical implications in the therapy of heart failure.
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PMID:alpha1-adrenergic receptors activate AMP-activated protein kinase in rat hearts. 1743 40

Chronic heart failure is debilitating, often fatal, expensive to treat and common. In most patients it is a late consequence of myocardial infarction (MI). The intracellular signals following infarction that lead to diminished contractility, apoptosis, fibrosis and ultimately heart failure are not fully understood but probably involve p38-mitogen activated protein kinases (p38), a family of serine/threonine kinases which, when activated, cause cardiomyocyte contractile dysfunction and death. Pharmacological inhibitors of p38 suppress inflammation and are undergoing clinical trials in rheumatoid arthritis, Chrohn's disease, psoriasis and surgery-induced tissue injury. In this review, we discuss the mechanisms, circumstances and consequences of p38 activation in the heart. The purpose is to evaluate p38 inhibition as a potential therapy for ischaemic heart disease.
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PMID:Potential of p38-MAPK inhibitors in the treatment of ischaemic heart disease. 1776 16

Tumor necrosis factor alpha (TNFalpha) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNFalpha induced ROS production, exerted a dual positive and negative action on [Ca(2+)] transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNFalpha responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNFalpha on [Ca(2+)] transient and cell fractional shortening. The positive effect of TNFalpha relied on TNFR2-dependent activation of the cPLA(2) activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA(2) redistribution and AA release, TNFalpha induced a time-dependent phosphorylation of ERK, MSK1, PKCzeta, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNFalpha while releasing TNFR2 pathways.
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PMID:TNFR1 and TNFR2 signaling interplay in cardiac myocytes. 1791 4

Recovery of intracellular Ca transients and fractional shortening during late phase acidosis are suggested to be associated with CaMKII-dependent processes of which phospholamban (PLB) phosphorylation may play an important role. To test whether increased expression levels of CaMKII may further enhance recovery, we investigated myocytes from CaMKIIdelta(C) transgenic (TG) mice (cytosolic localized CaMKII) having heart failure vs. wild-type littermates (WT). Furthermore, mouse and rabbit myocytes overexpressing CaMKIIdelta(C) using adenovirus-mediated gene transfer (vs. LacZ control) were investigated. Fractional shortening (% vs. resting cell length, % RCL) was assessed during control conditions (pH 7.4) and during acidosis (pH 6.5). Ca transients were measured using fluo-3 (DeltaF/F(0), 10 microM). In WT mouse myocytes, fractional shortening clearly recovered by 90% from 4.6+/-0.6 to 7.2+/-0.7% RCL during late acidosis. In parallel, Ca transients increased from 2.01+/-0.11 to 2.33+/-0.15 DeltaF/F(0). When blocking CaMKII (KN-93, 1 microM), recovery of Ca transients and shortening could be completely abolished. In contrast, in CaMKIIdelta(C) TG mouse myocytes shortening recovered only by 32% from 3.4+/-0.6 to 4.4+/-0.5% RCL (P<0.05 vs. WT using ANOVA). In parallel, Ca transients increased only slightly from 1.75+/-0.15 to 1.84+/-0.13 DeltaF/F(0) (P<0.05 vs. WT using ANOVA). In accordance, SR Ca content (measured by caffeine contractures, 10 mM) in WT significantly increased during late acidosis but not in CaMKIIdelta(C) TG mice. In contrast, in mouse and rabbit myocytes overexpressing CaMKIIdelta(C) by means of adenovirus-mediated gene transfer, recovery of fractional shortening and Ca transients was not impaired during late acidosis but even slightly improved vs. LacZ control (P<0.05 vs. CaMKIIdelta(C) using ANOVA for mouse and rabbit myocytes). This was associated with significantly increased SR Ca content during late acidosis in CaMKIIdelta(C) as compared to LacZ. CaMKII-dependent PLB Thr-17 phosphorylation, contributing to increased SR Ca uptake, was significantly increased in CaMKIIdelta(C) transfected rabbit myocytes vs. LacZ in the light of unchanged SR Ca ATPase and PLB protein expression. CaMKII inhibition completely prevented recovery of all parameters in both CaMKIIdelta(C) and LacZ. In summary and in contrast to our initial hypothesis, we showed for the first time that TG CaMKIIdelta(C) overexpression (i.e., chronic overexpression) in mice with heart failure clearly resulted in impaired recovery associated with impaired SR Ca loading during late acidosis vs. WT. This may be due to decreased SR Ca ATPase and PLB expression as reported previously. In contrast, adenovirus-mediated gene transfer of CaMKIIdelta(C) in mouse and rabbit myocytes (i.e., acute overexpression) did not result in impaired but even slightly improved recovery associated with increased SR Ca load during late acidosis as compared to LacZ. This most likely was due to higher PLB Thr-17 phosphorylation in CaMKIIdelta(C) myocytes. In conclusion, possible beneficial effects by therapeutical CaMKIIdelta(C) stimulation on the ability to recover from acidosis may be challenged by altered expression levels of its target proteins and should be carefully considered.
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PMID:Effects on recovery during acidosis in cardiac myocytes overexpressing CaMKII. 1795 Jul 50

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca(2+) handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)-adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) mice with C57BL6/J genetic background (3-5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser(2809)-RyR, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLN), phospho-Ser(16)-PLN, and phospho-Thr(17)-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and alpha(2A)/alpha(2C)ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, alpha(2A)/alpha(2C)ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, alpha(2A)/alpha(2C)ARKO mice displayed increased phospho-Ser(16)-PLN (76%) and phospho-Ser(2809)-RyR (49%). ET in alpha(2A)/alpha(2C)ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser(16)-PLN (30%) while it restored the expression of phospho-Ser(2809)-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca(2+) handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.
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PMID:Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice. 1797 26

Diaryl esters of alpha-aminophosphonates are a group of low molecular weight inhibitors of serine proteases. For over 30 years these molecules have captured the attention of biochemists and medicinal chemists due to their similarity to the transition state of peptide bond cleavage observed in enzymatic reactions (transition state analogs) as well as their high potency of action. High reactivity toward serine proteases and complete lack of activity against cysteine or threonine proteases give alpha-aminophosphonates great advantage over other classes of inhibitors such as chloromethyl ketones or peptidyl derivatives of ketoesters and ketoamides, which are known to react with serine and cysteine proteases. Moreover, the selectivity of alpha-aminophosphonates' action can be easily adjusted - even for serine proteases with similar specificity a small modification in the inhibitor structure could lead to absolute selectivity towards a particular enzyme. Furthermore alpha-aminophosphonate derivatives are successfully used as the activity based probes (ABP) for serine protease-like activity screening and as covalently reactive antigens for the development of catalytic antibodies (CAbs). The design of alpha-aminophosphonate diaryl ester inhibitors focuses on enzymes involved in the development and progression of pathophysiological states in living organisms. Examples include cancer growth and metastasis (urokinase-type plasminogen activator, uPA), diabetes or transplant rejection (dipeptidyl peptidase IV, DPPIV), osteoarthritis and lung injury (elastase) or heart failure (mast cell chymase). This review article focuses on the design of new alpha-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.
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PMID:Irreversible inhibition of serine proteases - design and in vivo activity of diaryl alpha-aminophosphonate derivatives. 1944 39

Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional Ser/Thr kinase that plays important roles in necrosis and apoptosis of cardiomyocytes. A major mechanism of cell necrosis is the opening of the mitochondrial permeability transition pore (mPTP), which consists of multiple protein subunits, including adenine nucleotide translocase (ANT). The threshold for mPTP opening is elevated by phosphorylation of GSK-3beta at Ser9, which reduces activity of this kinase. How inactivation of GSK-3beta suppresses mPTP opening has not been fully understood, but evidence to date suggests that preservation of hexokinase-II in the mPTP complex, inhibition of cyclophilin-D-ANT binding, inhibition of p53 and inhibition of ANT into the mitochondria are contributory. GSK-3beta phosphorylation is a step to which multiple protective signaling pathways converge, and thus GSK-3beta phosphorylation is crucial in cardioprotection of a variety of interventions against ischemia/reperfusion injury. Apoptosis of cardiomyocytes by pressure overload or ischemia/reperfusion is also suppressed by inactivation of GSK-3beta, in which reduced phosphorylation of p53, heat shock factor-1 and myeloid cell leukemia sequence-1 and inhibition of Bax translocation might be involved. Considering predominant roles of GSK-3beta in cardiomyocyte death, manipulation of this protein kinase is a promising strategy for myocardial protection in coronary artery disease and heart failure.
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PMID:GSK-3beta, a therapeutic target for cardiomyocyte protection. 1950 20


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