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)

Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
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PMID:Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging. 2007 77

The coxsackie-adenovirus receptor (CAR) is an adhesion molecule found at the intercalated disc of cardiomyocytes in association with other adherens and tight junction proteins. CAR expression is increased at cardiomyocyte junctions in patients with heart failure. It is not known what contribution elevated CAR expression makes to cardiac pathology. We generated a binary transgenic mouse enabling cardiac-restricted doxycycline-regulated expression of Flag-tagged murine CAR (mCAR(+)/alpha MtTA(+) mice). Myocardial CAR levels were increased 6-fold in mCAR(+)/alpha MtTA(+) mice, localizing to intercalated discs and sarcolemma. Well at birth, mCAR(+)/alpha MtTA(+) mice developed a severe cardiomyopathy and died by 4 weeks. Cardiomyocyte hypertrophy was evident at 1 week, with increased heart:body weight ratios by 3 weeks. Disorganization and degeneration of cardiomyocytes were evident with disrupted adherens junctions. Doxycycline administration turned off transgene expression and rescued mice from the development of the cardiomyopathic phenotype. In CAR-overexpressing mCAR(+)/alpha MtTA(+) mice, adherens junction proteins were abnormally expressed. N-cadherin protein levels were 83% lower in mCAR(+)/alpha MtTA(+) hearts vs controls at 1 week, with levels subsequently increased above controls at 3 weeks. beta-catenin expression was 90% and 135% above controls at 1 and 3 weeks, respectively. Nuclear translocation of beta-catenin in cardiomyocytes of mCAR(+)/alpha MtTA(+) mice was associated with increased c-myc RNA, a target of active beta-catenin known to be associated with cardiac hypertrophy. Our study is the first to demonstrate that increased CAR expression can induce a cardiomyopathy and supports a model whereby the pathogenesis is determined by CAR stimulated beta-catenin signaling, and/or disruption of the adherens junction.
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PMID:Cardiomyocyte-targeted overexpression of the coxsackie-adenovirus receptor causes a cardiomyopathy in association with beta-catenin signaling. 2014 15

Fibronectin type III domain-containing 5 protein (Fndc5) is an exercise hormone and its transcript profile in mouse showed high degree of expression in heart, skeletal muscle and brain. Our previous studies indicated a significant increase (approximately 10 fold) in mRNA level of Fndc5 when embryonic stem cells were differentiated into beating bodies. As a step closer to identify the involvement of Fndc5 in the process of cardiomyocyte differentiation, we generated a stably inducible transduced mouse embryonic stem cell (mESC) line that overexpressed Fndc5 following Doxycycline induction. Our results indicated that the overexpression of Fndc5 during spontaneous cardiac differentiation significantly increased not only at RNA levels for mesodermal markers but also at the transcriptional levels for cardiac progenitor and cardiac genes. These data suggest that Fndc5 may be involved in cardiomyocyte differentiation. Therefore, a new hope will be arisen for potential application of this myokine for regeneration of damaged cardiac tissues especially in cardiac failure.
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PMID:Induced expression of Fndc5 significantly increased cardiomyocyte differentiation rate of mouse embryonic stem cells. 2516 92

The brucellosis with multi-organ involvement in a patient with a history of the composite aortic graft (Bentall procedure) and Hepatitis B infection is rare. A 35-year-old man presented to us with fever and loss of consciousness. Four years ago, he was IDU and underwent cardiac surgery because of endocarditis. Recently lumbar spondylodiscitis was diagnosed. The Wright (1/320) and Coombs Wright tests (1/640) were positive. After CNS imaging, lumbar puncture was done. The CSF pleocytosis was lymphocyte dominant. In cardiac echocardiography, large vegetation on prosthetic aortic valve leaflets was seen. The brain MRI was reported abnormal. Treatment of brucellosis started with Ceftriaxone, Doxycycline, Rifampin and Gentamycin. After 4 days, he became oriented, and fever was disappeared then we continued the treatment for 16 days. The patient discharged and followed by daily phone calls. As symptoms of abdominal pain and jaundice were presented on the fifth day, he re-admitted. The patient expired because of hepatorenal and cardiac insufficiency. Drug side effects, activation of Hepatitis B and embolism of cardiac vegetation to other organs were suspected causes of death. We do not suggest medical therapy without cardiac surgery in such cases. When combination therapy is necessary for brucellosis in an HBsAg-positive patient, hepatitis virus activity should be assess by HBV-DNA PCR and the dose of drugs with known hepatotoxic effects such as rifampin and co-trimoxazole should be adjust. Combination therapy with quinolones instead of hepatoxic drugs is one of our suggustions.
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PMID:Brucellosis With Multi-Organ Involvement in a Patient With History of Composite Aortic Graft and Hepatitis B. 2803

Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo, and HF following experimental myocardial infarction (MI) in vivoMethods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca2+-regulatory genes, and induced hypertrophy without significant differences in Ca2+ transients or diastolic Ca2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF.Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF.
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PMID:Cardiac-specific inducible overexpression of human plasma membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury. 2948 97