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)

Using transgenesis as a paradigm, we show here that alpha1-adrenergic receptors (alpha1AR) play an important role in cardiac homeostasis. Cardiomyocyte-specific overexpression of the alpha(1B)AR subtype resulted in the development of dilated cardiomyopathy and death at ~9 mo of age with typical signs of heart failure. Histological analyses showed the enlargement of all four cardiac chambers and cardiomyocyte disarray in the failing hearts. Transgenic animals showed increased left ventricular areas, as assessed by echocardiography. In addition, a progressive decrease in left ventricular systolic function was revealed. The abundance and activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) were reduced, and the ratio of phospholamban to SERCA2 was increased. alpha-Myosin heavy chain (MHC) mRNA was less abundant in older transgenic ventricles, whereas beta-MHC was induced in the failing hearts. Titin mRNA abundance was decreased at 9 mo, whereas atrial natriuretic factor mRNA was elevated at all times. This model mimics structural and functional features of idiopathic dilated cardiomyopathy. The results of this study suggest that chronic alpha1AR activity is deleterious for cardiac function.
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PMID:Cardiac-directed overexpression of wild-type alpha1B-adrenergic receptor induces dilated cardiomyopathy. 1145

Patients with cardiac hypertrophy and heart failure display abnormally slowed myocardial relaxation, which is associated with downregulation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) gene expression. We previously showed that SERCA2 downregulation can be simulated in cultured neonatal rat ventricular myocytes (NRVM) by treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA). However, NRVM express three different PMA-sensitive PKC isoenzymes (PKCalpha, PKCepsilon, and PKCdelta), which may be differentially regulated and have specific functions in the cardiomyocyte. Therefore, in this study we used adenoviral vectors encoding wild-type (wt) and kinase-defective, dominant negative (dn) mutant forms of PKCalpha, PKCepsilon, and PKCdelta to analyze their individual effects in regulating SERCA2 gene expression in NRVM. Overexpression of wtPKCepsilon and wtPKCdelta, but not wtPKCalpha, was sufficient to downregulate SERCA2 mRNA levels, as assessed by Northern blotting and quantitative, real-time RT-PCR (69 +/- 7 and 61 +/- 9% of control levels for wtPKCepsilon and wtPKCdelta, respectively; P < 0.05 for each adenovirus; n = 8 experiments). Conversely, overexpression of all three dnPKCs appeared to significantly increase SERCA2 mRNA levels (dnPKCdelta > dnPKCepsilon > dnPKCalpha). dnPKCdelta overexpression produced the largest increase (2.8 +/- 1.0-fold; n = 11 experiments). However, PMA treatment was still sufficient to downregulate SERCA2 mRNA levels despite overexpression of each dominant negative mutant. These data indicate that the novel PKC isoenzymes PKCepsilon and PKCdelta selectively regulate SERCA2 gene expression in cardiomyocytes but that neither PKC alone is necessary for this effect if the other novel PKC can be activated.
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PMID:Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes. 1277 53

Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using beta-adrenergic receptor antagonists (beta-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of beta-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective beta-receptor blocker (5 mg. kg-1. day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), whereas Na+/Ca2+ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca2+ dynamics occurred within 2 wk of beta-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that beta-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.
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PMID:Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade. 1264 72

We have documented the effects of long-term endothelin receptor antagonism on intracellular Ca2+ regulation and Ca2+ regulatory protein expression in rat hearts with right ventricular hypertrophy without signs of heart failure. Rats were given either a single injection of monocrotaline (50 mg/kg, n=9) resulting in pulmonary hypertension-induced myocardial hypertrophy, or monocrotaline followed by daily administration of the endothelin subtype-A receptor antagonist 2-benzo(1,3)dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-Na (PD 155080, 50 mg/kg) over 9 weeks (n=8). Hearts from saline-injected rats served as controls (n=9). Monocrotaline-treated animals developed marked right-sided hypertrophy without fibrosis as evident from hydroxyproline measurements, systolic contractility was increased, fully compensating for the increased afterload, but diastolic function was impaired as evident from protracted relaxation and slowed diastolic intracellular Ca2+ handling (measured by aequorin bioluminescence). In hypertrophic hearts, quantitative immunoblotting analyses showed increased levels both of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and phosphorylated phospholamban, along with decreased levels of total phospholamban, which is in line with strengthened right ventricular systolic function. PD 155080 reversed abnormalities in Ca2+ handling, although SERCA and phospholamban protein levels were not altered (P=not significant versus monocrotaline group). Thus, endothelin-A receptor antagonism attenuates right ventricular remodeling and improves myocardial Ca2+ handling, but has no discernable effect on elevated expression of SERCA and phospholamban observed in hypertrophic hearts. These data indicate that the hypotensive action of PD 155080 is independent of its effects, if any, on SERCA and its regulation.
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PMID:Effect of endothelin antagonism on contractility, intracellular calcium regulation and calcium regulatory protein expression in right ventricular hypertrophy of the rat. 1472 13

Many cardiovascular disease states end in progressive heart failure. Changes in intracellular calcium handling, including a reduced activity of the sarcoplasmic reticulum calcium pump (SERCA), contribute to this contractile dysfunction. As the regulatory protein phospholamban can inhibit the calcium pump, we evaluated it as a potential target to improve cardiac function. In this study, we describe a recombinant antibody-based protein (PLN-Ab) that binds to the cytoplasmic domain of phospholamban. Fluorescence resonance energy transfer (FRET) studies suggest that PLN-Ab mimics the effects of phospholamban phosphorylation. PLN-Ab accelerated the decay of the calcium transient when expressed in neonatal rat and adult mouse ventricular cardiac myocytes. In addition, direct injection of adenovirus encoding PLN-Ab into the diabetic mouse heart enhanced contractility when measured in vivo by echocardiography and in ex vivo Langendorff perfused hearts. The PLN-Ab provides a novel therapeutic approach to improving contractility through in vivo expression of an antibody inside cardiac myocytes.
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PMID:A recombinant antibody increases cardiac contractility by mimicking phospholamban phosphorylation. 1518 Sep 62

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II-mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (approximately 45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.
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PMID:Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. 1599 12

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

One of the prominent markers of end-stage heart failure at the molecular level is a decrease in function and/or expression of the sarcoplasmic reticulum ATPase protein [sarco(endo)plasmic reticulum calcium-ATPase, SERCA]. It has been often postulated that a decrease in SERCA pump activity can contribute in a major way to decreased cardiac function. To establish a functional relationship, we assessed how alterations in SERCA activity level affect basic contractile function in healthy myocardium devoid of other significant molecular changes. We investigated baseline contractile function, frequency-dependent activation, and beta-adrenergic response in ultrathin trabeculae isolated from hearts of mice overexpressing SERCA (transgenic, TG), underexpressing SERCA2a (heterozygous knockout, Het), and their respective wild-type (WT) littermates. At physiological temperature and frequency, compared with their respective WT littermates, SERCA1a mice displayed increased developed force at frequencies of 4-8 Hz ( approximately 90% increase at 4 Hz) and force equal to WT mice at 10-14 Hz. Force development at 4 Hz in presence of 1 muM isoproterenol was similar in TG and WT mice. In Het mice, developed force was nearly identical at the lower end of the frequency range (4-8 Hz) but slightly depressed at higher frequency (P < 0.05 at 14 Hz). In presence of 1 muM isoproterenol, developed force at 4 Hz was equal to that in WT mice. Compared with normal levels, increased SERCA activity enhanced force development only at subphysiological frequencies. A reduction in SERCA activity only showed a depression of force at the higher frequency range. Thus generalizations regarding the correlation between SERCA activity and contractility can be highly ambiguous, because this relationship is critically dependent on other factors including stimulation frequency.
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PMID:Frequency-dependent contractile strength in mice over- and underexpressing the sarco(endo)plasmic reticulum calcium-ATPase. 1725 13

Heart failure has been identified as a serious international problem, in particular for aging groups, posing both an increasing number of patients on waiting lists in countries susceptible with Medicare systems and increasing financial burdens. It may be imperative to develop a marker that can identify such problems at an early stage. It is believed that certain proteins have crucial roles in early detection of cardiovascular disease, the number one killer in United Arab Emirates. This might be accomplished by recognition of unusual features in protein candidates. Phospholamban (PLB) is a 52 amino acid phosphoprotein which regulates the calcium pump of cardiac sarcoplasmic reticulum (SR). During muscle contraction, PLB inhibits the Ca<sup>++ </sup> pump. During muscle relaxation, it can be phosphorylated, removing the inhibition and allowing Ca<sup>++</sup> to be pumped back into SR. With the calcium pump disrupted, the heart muscle is probably weakened, resulting in congestive heart failure. Interleukin 6 (IL-6) is considered as a better predictor of heart attack in elderly people. It could serve as an early warning sign since its level increases early in the inflammatory process. Also, it has been established that myocyte enhancer factor 2A (MEF2A) plays a vital role in the development of cardiovascular problems like atherosclerosis and restenosis after angioplasty inflammation. In this paper, the resonance recognition method (RRM) has been employed to determine the characteristic frequencies of the above-mentioned proteins. It has been found that phospholamban and IL-6 share the same characteristic frequency, 0.3320 plusmn 0.0002 suggesting their common probable contribution to heart failure. Myocyte enhancer factor 2A does not share the same characteristic frequency. Hence, phospholamban is suggested as a highly probable early marker for cardiac problem detection.
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PMID:Phospholamban, a predicted candidate for early cardiac problem detection using signal processing techniques. 1728 92

Chronic alcohol ingestion leads to alcoholic cardiomyopathy manifested by ventricular dysfunction and heart failure. Although accumulation of reactive oxygen species may play a role in alcohol-induced heart injury, direct impact of enhanced antioxidant defense on pathogenesis of alcoholic cardiomyopathy has not been elucidated. This study was designed to examine the effect of transgenic overexpression of the free radical scavenger metallothionein on alcohol-induced cardiac contractile dysfunction. Wild-type FVB and metallothionein mice were placed on a 4% alcohol or control diet for 12 wk. Cardiac contractile function was evaluated in cardiomyocytes including peak shortening (PS), time-to-peak shortening, time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (+/-dL/dt), intracellular Ca2+ rise (change in fura-2 fluorescent intensity [DeltaFFI]) and intracellular Ca2+ decay rate. Intracellular Ca2+ cycling proteins including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), Na+-Ca2+ exchanger (NCX) and phospholamban were assessed using Western blot analysis. Alcohol intake depressed PS, +/-dL/dt, and DeltaFFI, increased baseline fura-2 fluorescence intensity (FFI), and prolonged intracellular Ca2+ decay and TR90, all of which with the exception of DeltaFFI were abrogated by metallothionein. Enhanced stimulating frequency caused lessened PS decline at 1.0 Hz from FVB ethanol group, which was not affected by metallothionein. Immunoblotting data showed reduced SERCA2a, NCX and phospholamban expression in FVB group consuming alcohol. All of these alcohol- induced changes in cardiac proteins were nullified by the metallothionein transgene. In summary, our findings suggest a beneficial role of antioxidants in alcohol-induced cardiomyocyte dysfunction.
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PMID:Cardiac overexpression of metallothionein attenuates chronic alcohol intake-induced cardiomyocyte contractile dysfunction. 1734 28


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