Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation plays a central role in the pathogenesis of atherosclerosis. This study investigated whether the proteasome inhibitor has the same preventive effect on the formation of accelerated atherosclerosis in rabbits with uremia compared with a NF-kappaB inhibitor. New Zealand white rabbits were subjected to five-sixths nephrectomy (chronic renal failure [CRF]) or to a sham operation. Rats in each group were randomly assigned into three subgroups (n = 24 in each group) and treated with repeated intramuscular injections of proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC for a specified period. Compared with sham rabbits, CRF rabbits displayed typical atherosclerotic changes (endothelial cell damage, intimal thickens, and appearance of foam cells). CRF rabbits had significantly higher levels of proteasome activity, NF-kappaB mRNA, protein, and DNA binding activity as well as tumor necrosis factor-a and proliferative cell nuclear antigen protein expression in aortic wall cells. CRF rabbits also showed lower levels of IkappaBalpha. Compared with CRF rabbits, CRF rabbits treatment with proteasome inhibitor MG132 showed restoration of IkappaBalpha mRNA and protein expression and decreased NF-kappaB DNA binding activity and tumor necrosis factor-a expression. Treatment with either proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC could reverse these pathologic changes in the aortic wall cells of CRF rabbits. A comparison between the inhibitory effects of the two treatments revealed no statistical difference. These results suggest that ubiquitin-proteasome activation play a pivotal role in the pathogenesis of uremia-accelerated atherosclerosis. The ubiquitin-proteasome signaling pathway in aortic cells may therefore be an important target for preventing uremia-accelerated atherosclerosis.
J Cardiovasc Pharmacol 2010 Feb
PMID:Preventive effect of a proteasome inhibitor on the formation of accelerated atherosclerosis in rabbits with uremia. 1993 80

In response to changes in workload, the heart grows or shrinks. Indeed, the myocardium is capable of robust and rapid structural remodeling. In the setting of normal, physiological demand, the heart responds with hypertrophic growth of individual cardiac myocytes, a process that serves to maintain cardiac output and minimize wall stress. However, disease-related stresses, such as hypertension or myocardial infarction, provoke a series of changes that culminate in heart failure and/or sudden death. At the other end of the spectrum, cardiac unloading, such as occurs with prolonged bed rest or weightlessness, causes the heart to shrink. In recent years, considerable strides have been made in deciphering the molecular and cellular events governing pro- and anti-growth events in the heart. Prominent among these mechanisms are those mediated by FoxO (Forkhead box-containing protein, O subfamily) transcription factors. In many cell types, these proteins are critical regulators of cell size, viability, and metabolism, and their importance in the heart is just emerging. Also in recent years, evidence has emerged for a pivotal role for autophagy, an evolutionarily conserved pathway of lysosomal degradation of damaged proteins and organelles, in cardiac growth and remodeling. Indeed, evidence for activated autophagy has been detected in virtually every form of myocardial disease. Now, it is clear that FoxO is an upstream regulator of both autophagy and the ubiquitin-proteasome system. Here, we discuss recent advances in our understanding of cardiomyocyte autophagy, its governance by FoxO, and the roles each of these plays in cardiac remodeling.
J Cardiovasc Transl Res 2010 Aug
PMID:FoxO, autophagy, and cardiac remodeling. 2057 43

The ubiquitin proteasome system plays a role in regulating protein activity and is integral to the turnover of damaged and worn proteins. In this review, we discuss the recently described relationship between the ubiquitin proteasome system and the cardiac creatine kinase/phosphocreatine shuttle, an essential component of adenosine triphosphate generation and energy shuttling within the heart. The ubiquitin ligase muscle ring finger-1 (MuRF1) binds creatine kinase, leading to its ubiquitination and possible degradation. Muscle ring finger-1 may also be integral in the regulation of creatine kinase activity in vivo. Because there is a close relationship between the cardiac creatine kinase/phosphocreatine shuttle activity and heart failure, these findings suggest that MuRF1's role in protein quality control of creatine kinase may be vital to the regulation and maintenance of cardiac energetics to protect against heart failure.
Trends Cardiovasc Med 2010 Jan
PMID:Cardiac muscle ring finger-1--friend or foe? 2068 72

Approximately one half to two thirds of newly synthesized apolipoprotein B (apoB) in Hep G2 cells (a human hepatoma cell line) is degraded. The intracellular degradation of apoB associated with the rough endoplasmic reticulum (ER) is reviewed in the context of our current understanding of proteasome-mediated degradation of ER-associated proteins. A model of hepatic apoB biogenesis is presented.
Trends Cardiovasc Med 1998 Jan
PMID:Hepatic apolipoprotein B biogenesis: an update. 2123 6

Protein quality control (PQC) senses and repairs misfolded/unfolded proteins and, if the repair fails, degrades the terminally misfolded polypeptides through an intricate collaboration between molecular chaperones and targeted proteolysis. Proteolysis of damaged proteins is performed primarily by the ubiquitin-proteasome system (UPS). Macroautophagy (commonly known as autophagy) may also play a role in PQC-associated proteolysis, especially when UPS function becomes inadequate. The development of a range of heart diseases, including bona fide cardiac proteinopathies and various forms of cardiac dysfunction has been linked to proteasome functional insufficiency (PFI). Both PFI and activation of autophagy have been observed in the heart of well-established mouse models of cardiac proteinopathy. A causal relationship between PFI and autophagic activation was suggested by a study using cultured cardiomyocytes but has not been established in the heart of intact animals. Taking advantage of an autophagy reporter, we demonstrated here that pharmacologically induced proteasome inhibition is sufficient to activate autophagy in cardiomyocytes in both intact animals and cell cultures, unveiling a potential cross-talk between the two major degradation pathways in cardiac PQC.
Am J Cardiovasc Dis 2011
PMID:Proteasome malfunction activates macroautophagy in the heart. 2208 94

Atrophic signaling elements of the ubiquitin-proteasome system (UPS) are involved in skeletal muscle wasting as well as pressure overload models of heart failure. In our prior experiments, we demonstrated a transcriptional downregulation of atrophy-inducing vascular E3 ubiquitin ligases in a toxic model of pulmonary hypertension where pulmonary artery and right ventricle (RV) hypertrophy are evident. Given the numerous reports of glucocorticoid activation of the UPS and the negative regulator of muscle mass, myostatin, we investigated the efficacy of dexamethasone to reverse monocrotaline (MCT)-induced pulmonary hypertension and augment atrogin-1 expression in both pulmonary arteries and myocardium. Dexamethasone caused significant reductions in body weight in combination with MCT. As predicted, MCT-induced pulmonary hypertension was evident by increases in RV systolic pressure, right ventricle to left ventricle plus septal weight ratios (RV/LVS) and arterial remodeling. MCT treatment significantly reduced both RV and PA atrogin-1 expression. Dexamethasone treatment reversed the MCT-induced pathological indices and restored RV atrogin-1 expression, but did not impact atrogin-1 expression in pulmonary arteries. Myostatin was poorly expressed in pulmonary arteries compared to the RV, and dexamethasone treatment increase RV myostatin in controls but not MCT-treated rats. These findings suggest that mechanisms independent of myostatin/atrogin-1 are responsible for glucocorticoid efficacy in this model of pulmonary hypertension.
Cardiovasc Toxicol 2012 Sep
PMID:Cardiac and vascular atrogin-1 mRNA expression is not associated with dexamethasone efficacy in the monocrotaline model of pulmonary hypertension. 2231 Nov 9

Vascular smooth muscle cell (VSMC) plasticity implies a capacity for rapid change and adaptability through processes requiring protein turnover. The ubiquitin-proteasome system (UPS) is at the core of protein turnover as the main pathway for the degradation of proteins related to cell-cycle regulation, signalling, apoptosis, and differentiation. This review briefly addresses some structural UPS aspects under the perspective of VSMC (patho)biology. The UPS loss-of-function promotes direct cell effects and many indirect effects related to the adaptation to apoptosis/survival signalling, oxidative stress, and endoplasmic reticulum stress. The UPS regulates redox homeostasis and is redox-regulated. Also, the UPS closely interacts with endoplasmic reticulum (ER) homeostasis as the effector of un/misfolded protein degradation, and ER stress is strongly involved in atherosclerosis. Inhibition of cell cycle-controlling ubiquitin ligases or the proteasome reduces VSMC proliferation and prevents modulation of their synthetic phenotype. Proteasome inhibition also strongly promotes VSMC apoptosis and reduces neointima. In atherosclerosis models, proteasome inhibitors display vasculoprotective effects and reduce inflammation. However, worsening of atherosclerosis or vascular dysfunction has also been reported. Proteasome inhibitors sensitize VSMC to increased ER stress-mediated cell death and suppress unfolded protein response signalling. Taken together, these observations show that the UPS has powerful effects in the control of VSMC phenotype and survival signalling. However, more profound knowledge of mechanisms is needed in order to render the UPS an operational therapeutic target.
Cardiovasc Res 2012 Jul 15
PMID:Physiological and pathological role of the ubiquitin-proteasome system in the vascular smooth muscle cell. 2245 13

Cardiomyocytes are terminally differentiated cells and thus do not have the ability to dilute damaged proteins and organelles by cell division. Thus, proteolytic and recycling systems within the cardiomyocyte are essential to maintain cardiac function. The major proteolytic systems in the cell are: the ubiquitin-proteasome system, autophagy, and calpain. The ubiquitin-proteasome system degrades specific proteins by labelling them with ubiquitin. Autophagy degrades cytosolic proteins and organelles; this is generally believed to be a non-specific type of degradation. Calpain is a Ca(2+)-sensitive cysteine protease that degrades intracellular substrates including cytoskeletal proteins, and participates in Ca(2+)-mediated intracellular processes. All three systems exist in the cardiomyocyte and play pivotal roles in maintaining cardiac function. However, there is still controversy regarding the role of each protein-degradation system in the heart. Our recent reports using cardiac-specific knockout mice have revealed the cardioprotective roles of autophagy and calpain in the development of heart failure. While these proteolytic systems exhibit distinct molecular mechanisms, they work cooperatively (one process can regulate another).
Cardiovasc Res 2012 Oct 01
PMID:Cooperation between proteolytic systems in cardiomyocyte recycling. 2284 2

As exemplified by desmin-related cardiomyopathy and myocardial ischemia/reperfusion injury, proteasome functional insufficiency plays an essential pathogenic role in the progression of cardiac diseases with elevated proteotoxic stress. Upregulation of p62/SQSTM1 and increased selective autophagy in cardiomyocytes may protect against proteotoxic stress in the heart. p62 may serve as a proteotoxic stress sensor, promote segregation and degradation of misfolded proteins by autophagy, and mediate the cross talk between the ubiquitin-proteasome system and autophagy.
Trends Cardiovasc Med 2011 Nov
PMID:p62 Stages an interplay between the ubiquitin-proteasome system and autophagy in the heart of defense against proteotoxic stress. 2290 70

During Pregnancy, heart develops physiological left ventricular hypertrophy as a result of the natural volume overload. Previously we have characterized the molecular and functional signature of heart hypertrophy during pregnancy. Cardiac hypertrophy during pregnancy is a complex process that involves many changes including in the signalling pathways, composition of extracellular matrix as well as the levels of sex hormones. This review summarises the recent advances and the new frontiers in the context of heart hypertrophy during pregnancy. In particular we focus on structural and extracellular matrix remodelling as well as signalling pathways in pregnancy-induced physiological heart hypertrophy. Emerging evidence shows that various microRNAs modulate key components of hypertrophy, therefore the role of microRNAs in the regulation of gene expression in pregnancy induced hypertrophy is also discussed. We also review the role of ubiquitin proteasome system, the major machinery for the degradation of damaged and misfolded proteins, in heart hypertrophy. The role of sex hormones in particular estrogen in cardiac remodeling during pregnancy is also discussed. We also review pregnancy-induced cardiovascular complications such as peripartum cardiomyopathy and pre-eclampsia and how the knowledge from the animal studies may help us to develop new therapeutic strategies for better treatment of cardiovascular diseases during pregnancy. Special emphasis has to be given to the guidelines on disease management in pregnancy.
Am J Cardiovasc Dis 2012
PMID:New frontiers in heart hypertrophy during pregnancy. 2293 89


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