Interferon-dependent immunoproteasome activity during mouse adenovirus type 1 infection.

The immunoproteasome is an inducible host mechanism that aids in the clearance of damaged proteins. The immunoproteasome also influences immune function by enhancing peptide presentation by MHC class I and promotes inflammation via IκB degradation and activation of NF-κB. We used mouse adenovirus type 1 (MAV-1) to characterize the role of the immunoproteasome in adenovirus pathogenesis.

Age influences inflammatory responses, hemodynamics, and cardiac proteasome activation during acute lung injury.

Background: Acute lung injury (ALI) is a significant source of morbidity and mortality in critically ill patients. Age is a major determinant of clinical outcome in ALI. The increased ALI-associated mortality in the older population suggests that there are age-dependent alterations in the responses to pulmonary challenge.

Assessment of cytokine-modulated proteasome activity.

This chapter presents two methods for assessment of proteasome function. The first is a modification of the standard fluorogenic peptide cleavage assay which takes into account the effect of ATP on proteasome activity. This method is described in both its macro and high throughput micro-assay forms.

Upregulation of proteasome activity rescues cardiomyocytes following pulse treatment with a proteasome inhibitor.

This study examined the hypothesis that cardiomyocyte metabolism is inherently linked to the Ubiquitin Proteasome System. Rat neonatal ventricular cardiomyocytes were pulse-treated with 5 αM lactacystin for 30 min, resulting in 95% loss of proteasome activity, and then maintained in culture for up to 24 h. Pulse-treatment resulted in 36% decrease in cardiomyocyte mitochondrial reductase activity by 8 h which improved to 15% by 24 h.

Impaired assembly and post-translational regulation of 26S proteasome in human end-stage heart failure.

Background: This study examined the hypothesis that 26S proteasome dysfunction in human end-stage heart failure is associated with decreased docking of the 19S regulatory particle to the 20S proteasome. Previous studies have demonstrated that 26S proteasome activity is diminished in human end-stage heart failure associated with oxidation of the 19S regulatory particle Rpt5 subunit. Docking of the 19S regulatory particle to the 20S proteasome requires functional Rpt subunit ATPase activity and phosphorylation of the α-type subunits.

The ubiquitin proteasome system and myocardial ischemia.

The ubiquitin proteasome system (UPS) has been the subject of intensive research over the past 20 years to define its role in normal physiology and in pathophysiology. Many of these studies have focused in on the cardiovascular system and have determined that the UPS becomes dysfunctional in several pathologies such as familial and idiopathic cardiomyopathies, atherosclerosis, and myocardial ischemia. This review presents a synopsis of the literature as it relates to the role of the UPS in myocardial ischemia.

The ubiquitin-proteasome system and cardiovascular disease.

Over the past decade, the role of the ubiquitin-proteasome system (UPS) has been the subject of numerous studies to elucidate its role in cardiovascular physiology and pathophysiology. There have been many advances in this field including the use of proteomics to achieve a better understanding of how the cardiac proteasome is regulated. Moreover, improved methods for the assessment of UPS function and the development of genetic models to study the role of the UPS have led to the realization that often the function of this system deviates from the norm in many cardiovascular pathologies.

Nicotinic acetylcholine receptor agonists attenuate septic acute kidney injury in mice by suppressing inflammation and proteasome activity.

Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI.

Proteasome functional insufficiency in cardiac pathogenesis.

The ubiquitin-proteasome system (UPS) is responsible for the degradation of most cellular proteins. Alterations in cardiac UPS, including changes in the degradation of regulatory proteins and proteasome functional insufficiency, are observed in many forms of heart disease and have been shown to play an important role in cardiac pathogenesis. In the past several years, remarkable progress in understanding the mechanisms that regulate UPS-mediated protein degradation has been achieved.

Enhancement of proteasome function by PA28α overexpression protects against oxidative stress.

The principal function of the proteasome is targeted degradation of intracellular proteins. Proteasome dysfunction has been observed in experimental cardiomyopathies and implicated in human congestive heart failure. Measures to enhance proteasome proteolytic function are currently lacking but would be beneficial in testing the pathogenic role of proteasome dysfunction and could have significant therapeutic potential.

Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress.

Macrophage migration inhibitory factor (MIF) is a multifunctional protein that exhibits an intrinsic thiol protein oxidoreductase activity and proinflammatory activities. In the present study to examine intracellular MIF redox function, exposure of MIF-deficient cardiac fibroblasts to oxidizing conditions resulted in a 2.3-fold increase (p < 0.

Myocardial ischemic preconditioning preserves postischemic function of the 26S proteasome through diminished oxidative damage to 19S regulatory particle subunits.

Rationale: The ubiquitin proteasome system (UPS) becomes dysfunctional as a result of ischemia/reperfusion (I/R), which may lead to dysregulation of signaling pathways. Ischemic preconditioning (IPC) may prevent dysregulation by preventing UPS dysfunction through inhibition of oxidative damage.

Objective: Examine the hypothesis that early IPC preserves postischemic UPS function thus facilitating prosurvival signaling events.

Decreased sensitivity associated with an altered formulation of a commercially available kit for detection of protein carbonyls.

Carbonylation is a commonly studied form of oxidative modification to proteins which can be conveniently detected using commercially available kits. The most common of these kits is the Oxyblot Protein Oxidation Detection Kit (Chemicon/Millipore). Over the past year we have observed severely diminished sensitivity of these kits which was shown to be a result of a change in the formulation of one of the components supplied in the kit.

Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.

Background: The ubiquitin proteasome system maintains a dynamic equilibrium of proteins and prevents accumulation of damaged and misfolded proteins, yet its role in human cardiac dysfunction is not well understood. The present study evaluated ubiquitin proteasome system function in human heart failure and hypertrophic cardiomyopathy (HCM).

Methods And Results: Proteasome function was studied in human nonfailing donor hearts, explanted failing hearts, and myectomy samples from patients with HCM.

The ubiquitin-proteasome system in myocardial ischaemia and preconditioning.

The ubiquitin-proteasome system (UPS) represents the major pathway for degradation of intracellular proteins. This article reviews the major components and configurations of the UPS including the 26S proteasome and 11S activated proteasome relevant to myocardial ischaemia. We then present the evidence that the UPS is dysfunctional during myocardial ischaemia as well as potential consequences of this, including dysregulation of target substrates, many of them active signalling proteins, and accumulation of oxidized proteins.

Caveolin and proteasome in tocotrienol mediated myocardial protection.

The effect of different isomers of tocotrienol was tested on myocardial ischemia reperfusion injury. Although all of the tocotrienol isomers offered some degree of cardioprotection, gamma-tocotrienol was the most protective as evident from the result of myocardial apoptosis. To study the mechanism of tocotrienol mediated cardioprotection, we examined the interaction and/or translocation of different signaling components to caveolins and activity of proteasome.

Upregulation of myocardial 11S-activated proteasome in experimental hyperglycemia.

This study examined the hypothesis that the ubiquitin proteasome system (UPS) degrades proteins damaged by exposure to hyperglycemia. Experimental hyperglycemia was induced in male rats by treatment with streptozotocin. After 30 days, echocardiography confirmed the presence of cardiomyopathy as ejection fraction, fractional shortening, and diastolic function (E/A ratio) were decreased, and chamber diameter was increased in hyperglycemic animals.

Cardioprotection with palm oil tocotrienols: comparision of different isomers.

A recent study from our laboratory indicated the cardioprotective ability of the tocotrienol-rich fraction (TRF) from red palm oil. The present study compared cardioprotective abilities of different isomers of tocotrienol against TRF as recently tocotrienol has been found to function as a potent neuroprotective agent against stroke. Rats were randomly assigned to one of the following groups: animals were given, by gavage, either 0.

Optimal determination of heart tissue 26S-proteasome activity requires maximal stimulating ATP concentrations.

The ubiquitin-proteasome system has been implicated in both cardiac physiology and pathophysiology. Research in this area has been hampered by the lack of a simple, reproducible method to assess 26S-proteasome peptidase activities. The current report demonstrates that one reason for lack of reproducibility is the myriad of ATP concentrations, many of them excessive, which have been used to stimulate peptidase activity.

The ubiquitin-proteasome system in cardiac physiology and pathology.

The ubiquitin-proteasome system (UPS) is the major nonlysosomal pathway for intracellular protein degradation, generally requiring a covalent linkage of one or more chains of polyubiquitins to the protein intended for degradation. It has become clear that the UPS plays major roles in regulating many cellular processes, including the cell cycle, immune responses, apoptosis, cell signaling, and protein turnover under normal and pathological conditions, as well as in protein quality control by removal of damaged, oxidized, and/or misfolded proteins. This review will present an overview of the structure, biochemistry, and physiology of the UPS with emphasis on its role in the heart, if known.

Proteasome mediates removal of proteins oxidized during myocardial ischemia.

Numerous proteins are known to be lost following myocardial ischemia/reperfusion yet little is known about the mediating proteinases. This study examines the hypothesis that proteasome plays a significant role in the removal of proteins oxidized during myocardial ischemia. Proteasome was inhibited by perfusing isolated rat hearts with buffer containing lactacystin, 2 micromol/L, for 10 min, which resulted in 51 and 42% decreases in 20S and 26S proteasome activities that persisted for a minimum of 90 min.

Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function: essential role of the proteasome.

This study examined the hypothesis that postischemic levels of oxidized and/or ubiquitinated proteins may be predictive of functional recovery as they may be indicative of activity of the 20S and/or 26S proteasomes, respectively. Subjecting isolated rat hearts to 15 min of ischemia had no effect on 20S- and 26S-proteasome activities; however, both were significantly (p < 0.05) decreased by 70% and 54%, respectively, following 30 min of ischemia and 60 min of reperfusion, changes associated with increased levels of protein carbonyls and ubiquitinated proteins.