The ubiquitin proteasome system and myocardial ischemia

Calise, Justine; Powell, Saul R.

doi:10.1152/ajpheart.00604.2012

Cited by 64 publications

(46 citation statements)

References 173 publications

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“…Neither the irreversible/␤ 5 -specific (epoxomicin) nor the reversible/nonspecific (MG132) proteasomal inhibitors altered the degree of RVH or hastened the development of RVF, suggesting that the failing RV is not responsive to further proteasomal inhibition in this model of RV failure. Nevertheless, future studies are needed to study the effect of inhibitors being developed against the induced isoforms of proteasomes (10).…”

Section: Discussionmentioning

confidence: 99%

“…Abnormalities in proteasomal function have been described well in models of left ventricular (LV) hypertrophy (LVH), ischemia-reperfusion (2,10,16), and dilated and desminrelated cardiomyopathies (13,49), as well as in human heart failure (47,49,72). However, studies have been contradictory, showing either increased or decreased proteasomal enzyme activity in the afterload stressed LV (31,43).…”

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confidence: 99%

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Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Rajagopalan

Zhao

Reddy

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28␣ subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight), RV dilation with septal shift, RV dysfunction, and clinical RVF. Proteasomal function (26S ␤5 chymotrypsin-like activity) was decreased 26% (P Ͻ 0.05). Protein expression of 19S subunit Rpt5 (P Ͻ 0.05), UCHL1 deubiquitinase (P Ͻ 0.0001), and Smurf1 E3 ubiquitin ligase (P Ͻ 0.01) were increased, as were polyubiquitinated proteins (P Ͻ 0.05) and free-ubiquitins (P ϭ 0.05). Pro-apoptotic Bax was increased (P Ͻ 0.0001), whereas anti-apoptotic Bcl-2 decreased (P Ͻ 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiacspecific proteasome overexpression partially improved survival. Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF, suggesting that UPS dysfunction contributes to RVF. ubiquitin; proteasome; right ventricle; cardiac hypertrophy; heart failure PATHOLOGIC HYPERTROPHY IS an important adaptation to stressors varying from ischemia to hypertension as well as many forms of congenital heart disease. Chronic hypertrophy-inducing stress can lead to fibrosis, decreased contractile function, and ultimately heart failure. Pressure overload hypertrophy is associated with a marked increase in protein synthesis at a rate exceeding degradation (57), the most dramatic the heart experiences since early development. Under normal circumstances, the proteins of the heart turn over at a rate that would replace all in 30 days (15,33,50). More than 70% of protein turnover is regulated by the ubiquitin-proteasome system (UPS) (18,56,74), involving signaling the target by covalent attachment of ubiquitin and degradation of tagged proteins by the 26S proteasome complex with release of ubiquitins by deubiquitinating enzymes. Three peptidase activities, chymotrypsin-like, trypsin-like, and caspase-like activities, have been assigned to the ␤ 5 , ␤ 2 , and ␤ 1 subunits, respectively, of the 20S core proteasomal complex, capped by 19S regulatory and/or 11S activator complexes. The UPS also interacts with lysosomal (autophagy dependent or independent) and other protease-specific pathways within the cardiomyocyte (17, 71)....

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Rajagopalan

Zhao

Reddy

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…28 We, therefore, tested our models for alterations in total protein ubiquitination. In the Langendorff-perfused mouse hearts, the amount of ubiquitinated proteins seemed unchanged between controls and I/R.…”

Section: Titin Ubiquitinationmentioning

confidence: 99%

Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction

Kötter

Kazmierowska

Andresen

et al. 2016

Circulation Research

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Rationale: Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post MI and identifying the processes that initiate transition to maladaptive remodeling are of major clinical interest. Objective: To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI. Methods and Results: Titin properties were analyzed in Langendorff-perfused mouse hearts after 20-minute ischemia/60-minute reperfusion (I/R), and mouse hearts that underwent ligature of the left anterior descending coronary artery for 3 or 10 days. Cardiac myocyte passive tension was significantly increased 1 hour after ischemia/reperfusion and 3 and 10 days after left anterior descending coronary artery ligature. The increased passive tension was caused by hypophosphorylation of the titin N2-B unique sequence and hyperphosphorylation of the PEVK (titin domain rich in proline, glutamate, valine, and lysine) region of titin. Blocking of interleukine-6 before left anterior descending coronary artery ligature restored titin-based myocyte tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the cytokine interleukine-6. We further demonstrate that the early remodeling processes 3 days after MI involve accelerated titin turnover by the ubiquitin–proteasome system. Conclusions: We conclude that titin-based cardiac myocyte stiffening acutely after MI is partly mediated by interleukine-6 and is an important mechanism of remote myocardium to adapt to the increased mechanical demands after myocardial injury.

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“…Three proteasome subunits (PSMB1, -A2, -A6) were among the CSF proteins with increased post-HI levels. Several studies have demonstrated reversible proteasome dysfunction secondary to oxidative damage after HI [18]. Dysregulation with decreased activity may lead to accumulation of damaged proteins, and promote neurodegenerative or neurodevelopmental disorders [19].…”

Section: Proteins Altered In Csfmentioning

confidence: 99%

Biomarker Discovery by Mass Spectrometry in Cerebrospinal Fluid and Plasma after Global Hypoxia-Ischemia in Newborn Piglets

et al. 2018

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Background: Biomarkers may qualify diagnosis, treatment allocation, and prognostication in neonatal encephalopathy. Biomarker development is challenged by competing etiologies, inter-individual genetic variability, and a lack of specific neonatal markers. To address these challenges, we used a standardized neonatal hypoxic-ischemic (HI) encephalopathy model with pre- and post-HI sampling of cerebrospinal fluid (CSF) and plasma. Objectives: The study aimed to identify novel candidate protein biomarkers of HI encephalopathy in a newborn piglet model in CSF and plasma. Methods: F_iO₂ was lowered to 4% in 6 newborn piglets, then adjusted over a 45-min period keeping the amplitude integrated-EEG < 7 µV to induce HI encephalopathy. CSF and plasma was sampled pre-HI and 2 h after HI, protein levels were then analyzed by mass spectrometry. Results: Protein levels after HI changed significantly for 18 CSF proteins and 37 plasma proteins. CSF and plasma data showed distinct information, although peptidyl-prolyl cis-trans isomerase A had elevated levels in both fluids. HI regulation involved functional groups such as the antioxidant system, cell proliferation, cell structure, and apoptosis. S100-A8, which increased the most in CSF (9.5 fold), is known to be involved in inflammatory and immune response and to be highly regulated during injury. In plasma, increased proteins included FABP1 (31.8 fold) and proteins with antioxidant (SOD1, GPX3) and lectin function (REG3A, LGALS3). Conclusions: In this exploratory study, we have identified candidate biomarkers for HI in CSF and plasma, many not previously associated with HI. Identified proteins are promising candidates for further validation in time series experiments and clinical studies.

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The ubiquitin proteasome system and myocardial ischemia

Cited by 64 publications

References 173 publications

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction

Biomarker Discovery by Mass Spectrometry in Cerebrospinal Fluid and Plasma after Global Hypoxia-Ischemia in Newborn Piglets

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