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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscle-specific RING finger protein 1 (MuRF1) is a sarcomere-associated protein that is restricted to cardiac and skeletal muscle. In skeletal muscle, MuRF1 is up-regulated by conditions that provoke atrophy, but its function in the heart is not known. The presence of a RING finger in MuRF1 raises the possibility that it is a component of the ubiquitin-proteasome system of protein degradation. We performed a yeast two-hybrid screen to search for interaction partners of MuRF1 in the heart that might be targets of its putative ubiquitin ligase activity. This screen identified troponin I as a MuRF1 partner protein. MuRF1 and troponin I were found to associate both in vitro and in vivo in cultured cardiomyocytes. MuRF1 reduced steady-state troponin I levels when coexpressed in COS-7 cells and increased degradation of endogenous troponin I protein in cardiomyocytes. The degradation of troponin I in cardiomyocytes was associated with the accumulation of ubiquitylated intermediates of troponin I and was proteasome-dependent. In vitro, MuRF1 functioned as a ubiquitin ligase to catalyze ubiquitylation of troponin I through a RING finger-dependent mechanism. In isolated cardiomyocytes, MuRF1 reduced indices of contractility. In cardiomyocytes, these processes may determine the balance between hypertrophic and antihypertrophic signals and the regulation of myocyte contractile responses in the setting of heart failure.
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PMID:Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I. 1560 79

Chronic heart failure is a clinical syndrome of cardiac origin, which affects various organ systems. It is associated with metabolic abnormalities leading to a catabolic syndrome in advanced stages of the disease. As in several other chronic diseases, skeletal muscle dysfunction and structural muscle abnormalities result in progressive muscle wasting and cachexia. These changes are accompanied by increased expression of proinflammatory cytokines, increased rate of apoptosis and activation of the proteolytic ubiquitin-proteasome pathway. Further, reduced expression of the local anabolic insulin-like growth factor-1 has been demonstrated in skeletal muscle of animals and patients with chronic heart failure. This suppression occurs in the presence of normal serum levels of insulin-like growth factor-1. In addition to catabolic effects of proinflammatory cytokines, these recent findings are consistent with reduced anabolism involving altered local insulin-like growth factor-1 levels in progressive muscle atrophy in chronic heart failure. This article describes local effects of insulin-like growth factor-1 on skeletal muscle function and morphology, its role in stem cell recruitment and muscle regeneration as well as its regulation in circumstances of muscle inflammation and wasting.
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PMID:Insulin-like growth factor-1 and muscle wasting in chronic heart failure. 1596 37

Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). However, less is known about the chronic effects of Akt activation in the heart, and, paradoxically, Akt is activated in samples from patients with chronic heart failure. We generated Tg mice with cardiac-specific expression of either activated (myristoylated [myr]) or dominant-negative (dn) Akt and assessed their response to IRI in an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction in functional recovery after IRI, no function was restored in any of the myr-Akt-Tg hearts. Moreover, infarcts were dramatically larger in myr-Akt-Tg hearts. Biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition of PI3K activity through both proteasome-dependent degradation of insulin receptor substrate-1 (IRS-1) and inhibition of transcription of IRS-1 as well as that of IRS-2. To test the functional significance of these signaling changes, we performed in vivo cardiac gene transfer with constitutively active PI3K in myr-Akt-Tg mice. Restoration of PI3K rescued function and reduced injury after IRI. These data demonstrate that PI3K-dependent but Akt-independent effectors are required for full cardioprotection and suggest a mechanism by which chronic Akt activation can become maladaptive.
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PMID:PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. 1607 47

Metabolic abnormalities develop in various chronic diseases and lead to progressive catabolism with decrements in the skeletal musculature that result in muscle atrophy. We investigated pathways of skeletal muscle proteolysis using an experimental model of chronic left-ventricular dysfunction. Skeletal muscle atrophy developed in wild-type mice 12 weeks following myocardial infarction accompanied by an increase in total protein ubiquitination and enhanced proteasome activity, activation of Foxo transcription factors, and robust induction of the ubiquitin-protein ligase atrogin-1/MAFbx. Further studies identified skeletal muscle myosin as a specific target of ubiquitin-mediated degradation in muscle atrophy. In contrast, transgenic overexpression of a local isoform of insulin-like growth factor-1 prevented muscle atrophy and increased proteasome activity, inhibited skeletal muscle activation primarily of Foxo4, and blocked the expression of atrogin-1/MAFbx. These results suggest that skeletal muscle atrophy occurs through increased activity of the ubiquitin-proteasome pathway. The inhibition of muscle atrophy by local insulin-like growth factor-1 provides a promising therapeutic avenue for the prevention of skeletal muscle wasting in chronic heart failure and potentially other chronic diseases associated with skeletal muscle atrophy.
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PMID:Transgenic overexpression of locally acting insulin-like growth factor-1 inhibits ubiquitin-mediated muscle atrophy in chronic left-ventricular dysfunction. 1614 Nov 15

The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation.
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PMID:Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice. 1640 36

Proteasomes are the main non-lysosomal multicatalytic protease complexes that are involved in the degradation of most intracellular proteins. The substrate proteins are marked by ubiquitin, which serves as a tag for their regulated proteasomal destruction. One major function of the ubiquitin-proteasome system (UPS) is to prevent accumulation of non-functional, potentially toxic proteins. Moreover, it has become clear that the UPS is involved in most aspects of eukaryotic biology, such as intracellular signaling, transcriptional control, or regulation of cell death. Recent studies demonstrated that the UPS regulates receptor internalization, hypertrophic response, apoptosis, and tolerance to ischemia and reperfusion in cardiomyocytes. Since structural remodeling of the myocardium, ischemia-reperfusion injury, and myocardial cell loss are important components in the genesis of progressive heart failure, these findings suggest a pathophysiological role of the UPS. This review briefly summarizes present knowledge about structure and function of the proteasome in the heart and discusses the relevance of the UPS for cardiac diseases.
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PMID:The ubiquitin-proteasome system: focus on the heart. 1649 85

Monocyte chemoattractant protein-1 (MCP-1; CCL2)-mediated inflammation plays a critical role in the development of ischemic heart disease (IHD). However, the gene expression changes caused by signal transduction, triggered by MCP-1 binding to its receptor CCR2, and their possible role in the development of IHD are not understood. We present evidence that MCP-1 binding to CCR2 induces a novel transcription factor (MCP-induced protein [MCPIP]) that causes cell death. Gene microarray analysis showed that when expressed in hiuman embryonic kidney 293 cells, MCPIP induced apoptotic gene families before causing cell death. Mutagenesis studies showed that the structural features required for transcription factor-like activity were also required for causing cell death. Activation of caspase-3 was detected after MCPIP transfection and Z-VAD-fmk partially inhibited cell death. Cardiomyocyte-targeted expression of MCP-1 in mice caused death by heart failure at 6 months of age. MCPIP expression increased in parallel with the development of ventricular dysfunction. In situ hybridization showed the presence of MCPIP transcripts in the cardiomyocytes and immunohistochemistry showed that MCPIP was associated with the cardiomyocyte nuclei of apoptotic cardiomyocytes. CCR2 expression in cardiomyocytes increased with the development of IHD. MCPIP production induced by MCP-1 binding to CCR2 in the cardiomyocytes is probably involved in the development of IHD in this murine model. MCPIP transcript levels were much higher in the explanted human hearts with IHD than with nonischemic heart disease. These results provide a molecular insight into how chronic inflammation and exposure to MCP-1 contributes to heart failure and suggest that MCPIP could be a potential target for therapeutic intervention.
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PMID:Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. 1669 Aug 87

Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in initiating coronary heart disease by recruiting monocytes/macrophages to the vessel wall. Transgenic mice with cardiac-specific expression of MCP-1 manifest cardiac inflammation and develop heart failure. The pathways mediating the detrimental effects of MCP-1 expression have not been defined. We postulate that the Fas ligand (FasL) derived from the infiltrating mononuclear cells causes death of cardiac cells resulting in the development of heart failure. Here, we tested this hypothesis by determining whether inhibition of FasL function through cardiac-specific expression of soluble Fas (sFas) would rescue the MCP-1 transgenic mice from developing heart failure. We generated mice with cardiac-specific expression of sFas and double homozygous transgenic mice that express both MCP-1 and sFas. Cardiac-specific expression of sFas in MCP mice, in fact, inhibited apoptosis of infiltrating mononuclear cells, normalized circulating C-reactive protein (CRP) levels, and prevented macrophage activation as well as production of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in the hearts. sFas expression resulted in restoration of cardiac structure, preservation of cardiac function, and a significant prolongation of survival of MCP mice. These results demonstrate that FasL released from infiltrating mononuclear cells plays a critical role in the detrimental effects of MCP-1 expression, and suggest that Fas/FasL signaling represents a novel therapeutic target for heart failure.
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PMID:Targeted cardiac expression of soluble Fas prevents the development of heart failure in mice with cardiac-specific expression of MCP-1. 1667 47

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 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


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