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)

Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. The transcription factor GATA4 is essential for cardiac homeostasis, and its protein levels are dramatically reduced in the heart in response to diverse pathologic stresses. In this study, we investigated if hyperglycemia affects GATA4 expression in cardiomyocytes and if enhancing GATA4 signaling could attenuate hyperglycemia-induced cardiomyocyte injury. In cultured rat cardiomyocytes, high glucose (HG, 25 or 40 mm) markedly reduced GATA4 protein levels as compared with normal glucose (NG, 5.5 mm). Equal amount of mannitol did not affect GATA4 protein expression (NG, 100 +/- 12%; mannitol, 97 +/- 8%, versus HG, 43 +/- 16%, p < 0.05). The GATA4 mRNA content, either steady-state or polysome-associated, remained unchanged. HG-induced GATA4 reduction was reversed by MG262, a specific proteasome inhibitor. HG did not activate the ubiquitin proteasome system (UPS) in cardiomyocytes as indicated by a UPS reporter, nor did it increase the peptidase activities or protein expression of the proteasomal subunits. However, the mRNA levels of ubiquitin-protein isopeptide ligase (E3) carboxyl terminus of Hsp70-interacting protein (CHIP) were markedly increased in HG-treated cardiomyocytes. CHIP overexpression promoted GATA4 protein degradation, whereas small interfering RNA-mediated CHIP knockdown prevented HG-induced GATA4 depletion. Moreover, overexpression of GATA4 blocked HG-induced cardiomyocyte death. Also, GATA4 protein levels were diminished in the hearts of streptozotocin and db/db diabetic mice (44 +/- 7% and 67 +/- 13% of control, p < 0.05), which correlated with increased CHIP mRNA abundance. In summary, increased GATA4 protein degradation may be an important mechanism that contributes to hyperglycemic cardiotoxicity.
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PMID:Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury. 1752 55

We tested the possibility that proteasome inhibition may reverse preexisting cardiac hypertrophy and improve remodeling upon pressure overload. Mice were submitted to aortic banding and followed up for 3 wk. The proteasome inhibitor epoxomicin (0.5 mg/kg) or the vehicle was injected daily, starting 2 wk after banding. At the end of the third week, vehicle-treated banded animals showed significant (P<0.05) increase in proteasome activity (PA), left ventricle-to-tibial length ratio (LV/TL), myocyte cross-sectional area (MCA), and myocyte apoptosis compared with sham-operated animals and developed signs of heart failure, including increased lung weight-to-TL ratio and decreased ejection fraction. When compared with that group, banded mice treated with epoxomicin showed no increase in PA, a lower LV/TL and MCA, reduced apoptosis, stabilized ejection fraction, and no signs of heart failure. Because overload-mediated cardiac remodeling largely depends on the activation of the proteasome-regulated transcription factor NF-kappaB, we tested whether epoxomicin would prevent this activation. NF-kappaB activity increased significantly upon overload, which was suppressed by epoxomicin. The expression of NF-kappaB-dependent transcripts, encoding collagen types I and III and the matrix metalloprotease-2, increased (P<0.05) after banding, which was abolished by epoxomicin. The accumulation of collagen after overload, as measured by histology, was 75% lower (P<0.05) with epoxomicin compared with vehicle. Myocyte apoptosis increased by fourfold in hearts submitted to aortic banding compared with sham-operated hearts, which was reduced by half upon epoxomicin treatment. Therefore, we propose that proteasome inhibition after the onset of pressure overload rescues ventricular remodeling by stabilizing cardiac function, suppressing further progression of hypertrophy, repressing collagen accumulation, and reducing myocyte apoptosis.
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PMID:Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload. 1870 39

Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant disorder that was recently identified as being caused by mutations in the VCP (p97 or CDC48) gene which plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retro translocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. Approximately 90% of the affected persons in the study have myopathy or muscle weakness particularly of the shoulder and hip girdles, which can lead to loss of walking ability and even death by complications of respiratory and cardiac failure. About half of affected study participants have Paget disease of bone characterized by abnormal rates of bone growth that can result in bone pain, enlargement and fractures. Findings of premature FTD affecting behavior and personality are seen in a third of affected individuals. Within 20 IBMPFD families whose data was analyzed for this study, ten missense mutations have been identified, the majority of which are located in the N-terminal ubiquitin binding domain. Inclusions seen in the muscle, brain and heart in VCP disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis.
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PMID:VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. 1884 50

The purpose of this review is to enlighten the mechanisms of skeletal muscle dysfunction in heart failure. The muscle hypothesis suggests that chronic heart failure (CHF) symptoms, dyspnoea and fatigue are due to skeletal muscle alterations. Hyperventilation due to altered ergoreflex seems to be the cause of shortness of breath. Qualitative and quantitative changes occurring in the skeletal muscle, such as muscle wastage and shift from slow to fast fibers type, are likely to be responsible for fatigue. Mechanisms leading to muscle wastage in chronic heart failure, include cytokine-triggered skeletal muscle apoptosis, but also ubiquitin/proteasome and non-ubiquitin-dependent pathways. The regulation of fibre type involves the growth hormone/insulin-like growth factor 1/calcineurin/ transcriptional coactivator PGC1 cascade. The imbalance between protein synthesis and degradation plays an important role. Protein degradation can occur through ubiquitin-dependent and non-ubiquit-independent pathways. Systems controlling ubiquitin/ proteasome activation have been described. These are triggered by tumour necrosis factor and growth hormone/ insulin-like growth factor 1. However, an important role is played by apoptosis. In humans, and experimental models of heart failure, programmed cell death has been found in skeletal muscle and interstitial cells. Apoptosis is triggered by tumour necrosis factor and in vitro experiments have shown that it can be induced by its second messenger sphingosine. Apoptosis correlates with the severity of the heart failure syndrome. It involves activation of caspases 3 and 9 and mitochondrial cytochrome c release. Sarcomeric protein oxidation and its consequent contractile impairment can form another cause of skeletal muscle dysfunction in CHF.
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PMID:Physiological basis for contractile dysfunction in heart failure. 1899 74

Cardiac cachexia as a terminal stage of chronic heart failure carries a poor prognosis. The definition of this clinical syndrome has been a matter of debate in recent years. This review describes the ongoing discussion about this issue and the complex pathophysiology of cardiac cachexia and chronic heart failure with particular focus on immunological, metabolic, and hormonal aspects at the intracellular and extracellular level. These include regulators such as neuropeptide Y, leptin, melanocortins, ghrelin, growth hormone, and insulin. The regulation of feeding is discussed as are nutritional aspects in the treatment of the disease. The mechanisms of wasting in different body compartments are described. Moreover, we discuss several therapeutic approaches. These include appetite stimulants like megestrol acetate, medroxyprogesterone acetate, and cannabinoids. Other drug classes of interest comprise angiotensin-converting enzyme inhibitors, beta-blockers, anabolic steroids, beta-adrenergic agonists, anti-inflammatory substances, statins, thalidomide, proteasome inhibitors, and pentoxifylline.
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PMID:Cardiac cachexia: a systematic overview. 1906 14

Impaired functioning of the gastrointestinal system may also contribute to malnutrition and cardiac cachexia (CC) in patients with chronic heart failure (CHF). Targets for future interventions include the deranged hormonal systems involved in energy balance as well as malabsorption from the gut and dietary supplementation. Other targets are the inhibition of proteasome-dependent protein degradation and the direct inhibition of pro-inflammatory pathways. The beneficial effects of ACE inhibitors, aldesterone inhibitors and beta-blockers in preventing or delaying the collagen deposition in the small intestine wall need to be elucidated. We strongly believe that by improving our understanding of the role of the gut in CC will lead to the development of novel therapeutic strategies in the near future.
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PMID:The small intestine: a critical linkage in pathophysiology of cardiac cachexia. 2111 52

Cardiomyopathies represent an important cause of cardiovascular morbidity and mortality due to heart failure, arrhythmias, and sudden death. Most forms of hypertrophic cardiomyopathy (HCM) are familial with an autosomal-dominant mode of inheritance. Over the last 20 years, the genetic basis of the disease has been largely unravelled. HCM is considered as a sarcomeropathy involving mutations in sarcomeric proteins, most often beta-myosin heavy chain and cardiac myosin-binding protein C. 'Missense' mutations, more common in the former, are associated with dysfunctional proteins stably integrated into the sarcomere. 'Nonsense' and frameshift mutations, more common in the latter, are associated with low mRNA and protein levels derived from the diseased allele, leading to haploinsufficiency of the remaining healthy allele. The two quality control systems responsible for the removal of the affected mRNAs and proteins are the nonsense-mediated mRNA decay (NMD) and the ubiquitin-proteasome system (UPS), respectively. This review discusses clinical and genetic aspects of HCM and the role of NMD and UPS in the regulation of mutant proteins, evidence for impairment of UPS as a pathogenic factor, as well as potential therapies for HCM.
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PMID:The ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy. 1961 24

The cardiac proteasome is a complex, heterogeneous, and dynamic organelle. Its function is regulated by its molecular organization, post-translational modifications, and associated partner proteins. Pressure overload, ischaemic heart disease, or genetic mutations in contractile proteins can cause heart failure, during which misfolded protein levels are elevated. At the same time, numerous interconnected signal transduction pathways are activated that may modulate any of the three proteasomal regulatory mechanisms mentioned above, resulting in functional changes in cardiac proteasomes. Many lines of evidence support the important role of the ubiquitin-proteasome system (UPS) in the development of heart diseases. Many researchers have focused on the UPS, applying new drug discovery methods not only in the field of cancer research but also in cardiovascular fields such as cardiac hypertrophy and ischaemic heart diseases. More understanding of UPS in the pathophysiology of heart diseases will lead to new routes for therapy.
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PMID:Functional alterations of cardiac proteasomes under physiological and pathological conditions. 1968 34

Protein quality control (PQC) depends on elegant collaboration between molecular chaperones and targeted proteolysis in the cell. The latter is primarily carried out by the ubiquitin-proteasome system, but recent advances in this area of research suggest a supplementary role for the autophagy-lysosomal pathway in PQC-related proteolysis. The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which belongs to a family of cardiac diseases caused by expression of aggregation-prone proteins in cardiomyocytes. Cardiac proteasome functional insufficiency (PFI) is best studied in desmin-related cardiomyopathy, a bona fide cardiac proteinopathy. Emerging evidence suggests that many common forms of cardiomyopathy may belong to proteinopathy. This review focuses on examining current evidence, as it relates to the hypothesis that PFI impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathies to heart failure.
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PMID:The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective. 1969 71

Virus-induced chronic inflammation, autoimmune processes and impaired protein quality control may be involved in the pathogenesis of dilated cardiomyopathy (DCM). The ubiquitin-proteasome system is important in the modulation of inflammatory processes and the immune response. Proteasomes were identified as targets of a humoral autoimmune response in systemic inflammatory diseases, which provoked us to investigate anti-proteasomal immunity in DCM in detail: a total of 90 DCM patients with impaired left-ventricular function (LVEF < or = 45%) were enrolled in this study. Autoimmune response to cardiac proteasomes was found to be enhanced in DCM patients, revealing the detection of predominantly alpha subunits of the 20S proteasome complex. Proteasome antibody (ProtAb) levels were found to be particularly enhanced at stages of advanced heart failure: moderately decreased LVEF and considerably increased NT-pro BNP levels were observed in DCM patients who tested positive for ProtAb (P < 0.05). A linear regression model suggested a link between the detection of cardiotropic viruses in endomyocardial biopsies and anti-proteasomal immunity (P < 0.01). Likewise, ProtAb levels were enhanced in a murine model of chronic enterovirus myocarditis. Our data also point to a potential interaction of ProtAb with the cell surface: ProtAb exerted negative inotropic effects in field-stimulated cardiomyocytes. In conclusion, humoral autoreactive anti-proteasome immune responses appear to be enhanced in DCM. Viral infection of the myocardium may be linked to the induction of anti-proteasomal immunity in DCM.
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PMID:Humoral anti-proteasomal autoimmunity in dilated cardiomyopathy. 1982 54


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