Abstract:
RATIONALE:The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine. OBJECTIVE:Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway. METHODS AND RESULTS:Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated Molcn1 silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice. CONCLUSIONS:(1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.
journal_name
Circ Resjournal_title
Circulation researchauthors
Pan B,Li J,Parajuli N,Tian Z,Wu P,Lewno MT,Zou J,Wang W,Bedford L,Mayer RJ,Fang J,Liu J,Cui T,Su H,Wang Xdoi
10.1161/CIRCRESAHA.119.316007subject
Has Abstractpub_date
2020-07-31 00:00:00pages
502-518issue
4eissn
0009-7330issn
1524-4571journal_volume
127pub_type
杂志文章abstract::We have investigated the actions of vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) on the pacemaker current (I(f)) in canine Purkinje fibers. On voltage pulses to the middle of the I(f) activation range, VIP reversibly increases I(f), whereas NPY reversibly decreases I(f). A three-pulse voltage protocol ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.1.157
更新日期:1994-01-01 00:00:00
abstract::Originally identified as moderate biological modifiers, microRNAs have recently emerged as powerful regulators of diverse cellular processes with especially important roles in disease and tissue remodeling. The rapid pace of studies on microRNA regulation and function necessitates the development of suitable technique...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.110.227496
更新日期:2011-01-21 00:00:00
abstract::Tropomyosin (TM) is an integral component of the thin filament in muscle fibers and is involved in regulating actin-myosin interactions. TM is encoded by a family of four alternatively spliced genes that display highly conserved nucleotide and amino acid sequences. To assess the functional and developmental significan...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.82.1.116
更新日期:1998-01-09 00:00:00
abstract::Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000204825.66410.0b
更新日期:2006-03-03 00:00:00
abstract::Whole-cell Ca2+ channel currents were recorded from isolated single canine Purkinje and ventricular cells to determine whether there were multiple types of Ca2+ channels in these two cell types, as in many other excitable tissues. The experimental conditions were such that currents other than Ca2+ channel currents wer...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.6.1735
更新日期:1989-12-01 00:00:00
abstract::Understanding the molecular interactions among components of cardiac Z-discs and their role in signaling has become pivotal in explaining long- and short-term regulation of cardiac function. In striated muscle, the ends of the thin filaments from opposing sarcomeres overlap and are cross-linked by an elaborate array o...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.RES.0000116143.74830.A9
更新日期:2004-02-20 00:00:00
abstract::Heart failure is associated with death of cardiomyocytes leading to loss of contractility. Previous studies using membrane-targeted Akt (myristolated-Akt), an enzyme involved in antiapoptotic signaling, showed inhibition of cell death and prevention of pathogenesis induced by cardiomyopathic stimuli. However, recent s...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000124394.01180.BE
更新日期:2004-04-16 00:00:00
abstract::Our objective was to test the hypotheses that 1) myoplasmic [Ca2+] is the primary determinant of crossbridge phosphorylation and that 2) phosphorylation is the primary determinant of crossbridge interactions with the thin filament in swine carotid arterial smooth muscle. We tested these hypotheses by evaluating the re...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.63.3.593
更新日期:1988-09-01 00:00:00
abstract::Mechanisms of denervation supersensitivity to sympathomimetic amines were studied in conscious animals. Norepinephrine, 0.1 micrograms/kg, increased left ventricular dP/dt significantly more (4208 +/- 828 mm Hg/sec) in dogs with cardiac denervation than in intact dogs (1029 +/- 280 mm Hg/sec), P less than 0.01, wherea...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.57.1.55
更新日期:1985-07-01 00:00:00
abstract::Vascular dysfunction in diabetes is attributed to lack of bioavailable nitric oxide (NO) and is postulated as a primary cause of small vessel complications as a result of poor glycemic control. Although it has been proposed that NO is bound by red blood cells (RBCs) and can induce relaxation of blood vessels distal to...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000122044.21787.01
更新日期:2004-04-16 00:00:00
abstract::Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remod...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000261352.81736.37
更新日期:2007-03-30 00:00:00
abstract:RATIONALE:Overexpression of muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, induces proteasomal degradation in cardiomyocytes. The role of endogenous MAFbx in regulating cardiac hypertrophy and failure remains unclear. OBJECTIVE:We investigated the role of MAFbx in regulating cardiac hypertrophy and fu...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.110.238717
更新日期:2011-07-08 00:00:00
abstract::Physiological or pathological stresses and strains produce longer or wider muscle cells, but resting sarcomere length remains constant. Our goal was to investigate the cellular mechanisms for controlling this optimal, resting sarcomere length. To do so, we cultured neonatal rat cardiomyocytes on microfabricated peg-an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000121101.32286.C8
更新日期:2004-03-19 00:00:00
abstract::Prolongation of the action potential has been postulated to be a major reason for the altered diastolic relaxation of the heart in patients with severe heart failure. To investigate the electrophysiological basis for this action potential prolongation in terminal heart failure, K+ currents were recorded in single vent...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.2.379
更新日期:1993-08-01 00:00:00
abstract::This study was designed to determine if opioids were detectable in cerebrospinal fluid (CSF) and if these concentrations were altered by hemorrhagic hypotension. This study was further designed to determine the effects of topically administered opioids on pial arteriolar diameter during normotension and hypotension. C...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.4.922
更新日期:1991-04-01 00:00:00
abstract::We carried out a systematic study on the effects of elevating [K]o on the properties of a transient outward potassium channel encoded by a cardiac cDNA (RHK1) and compared them with those on two Shaker potassium channels (H-4 and H-37). The amino acid sequences of all three channels are known, and their structure-func...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.3.657
更新日期:1992-09-01 00:00:00
abstract:RATIONALE:Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex proces...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.119.315804
更新日期:2020-02-28 00:00:00
abstract::The effects of mechanical factors on nuclear factor (NF)-kappaB activation and its potential functional roles have been very little explored in the intact vessel. Thus, we chose to study the regulation of NF-kappaB by intraluminal pressure using an organ culture model of mouse carotid arteries maintained at 80 or 150 ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000086942.13523.88
更新日期:2003-08-08 00:00:00
abstract:RATIONALE:Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated. OBJECTIVE:We studied the molecular mechanism mediating the effect of GSK-3β acti...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.249532
更新日期:2011-08-19 00:00:00
abstract:RATIONALE:Endothelial colony forming cells (ECFCs) or late blood outgrowth endothelial cells can be isolated from human cord or peripheral blood, display properties of endothelial progenitors, home into ischemic tissues and support neovascularization in ischemic disease models. OBJECTIVE:To assess the functions of CYT...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.118.313645
更新日期:2019-01-18 00:00:00
abstract::Changes in cardiac filling pressure (central venous pressure) were measured following carotid occlusion and infusions of catecholamines in awake dogs while cardiac output was held constant. After carotid occlusion in dogs with vagi blocked, central venous pressure increased about 0.8 mm Hg (an estimated decrease in va...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.55.4.440
更新日期:1984-10-01 00:00:00
abstract::Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accura...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/RES.0000000000000110
更新日期:2016-08-19 00:00:00
abstract::Spatial and temporal organization of signal transduction is coordinated through the segregation of signaling enzymes in selected cellular compartments. This highly evolved regulatory mechanism ensures the activation of selected enzymes only in the vicinity of their target proteins. In this context, cAMP-responsive tri...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.111.262899
更新日期:2012-08-03 00:00:00
abstract::Our previous studies suggested that enhanced fibronectin mRNA translation in ductus arteriosus compared with aortic smooth muscle cells is related to increased expression of light chain 3 (LC3) of microtubule-associated protein 1, which binds an AU-rich element in the 3' untranslated region of fibronectin mRNA. We the...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.83.5.481
更新日期:1998-09-07 00:00:00
abstract:RATIONALE:Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during a...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.118.312804
更新日期:2018-10-26 00:00:00
abstract:RATIONALE:ASK1-interacting protein-1 (AIP1), a Ras GTPase-activating protein family member, is highly expressed in endothelial cells and vascular smooth musccells (VSMCs). The role of AIP1 in VSMCs and VSMC proliferative disease is not known. OBJECTIVE:We used mouse graft arteriosclerosis models characterized by VSMC ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.248245
更新日期:2011-08-05 00:00:00
abstract::Glibenclamide, one of the antidiabetic sulfonylureas, is known to block ATP-dependent K+ channels. We used this drug to determine to what extent K+ loss from acutely ischemic myocardium is mediated via these channels. We also investigated whether glibenclamide would influence ischemic arrhythmias. Isolated rat hearts ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.2.478
更新日期:1990-02-01 00:00:00
abstract::Raising the hepatic venous pressure experimentally duplicates the type of hepatic congestion seen in many clinical situations including congestive heart failure. Venous pressure was controlled using a hepatic venous long circuit preparation and was raised by 6 cm blood (4.7 mm Hg) or 10 cm (7.8 mm Hg). Total splanchni...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.41.6.787
更新日期:1977-12-01 00:00:00
abstract::Life threatening ventricular arrhythmias leading to sudden cardiac death are a major cause of morbidity and mortality. In the absence of structural heart disease, these arrhythmias, especially in the younger population, are often an outcome of genetic defects in specialized membrane proteins called ion channels. In th...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.118.311209
更新日期:2018-07-06 00:00:00
abstract::Cyclic nucleotide phosphodiesterases regulate cAMP-mediated signaling by controlling intracellular cAMP content. The cAMP-hydrolyzing activity of several families of cyclic nucleotide phosphodiesterases found in human heart is regulated by cGMP. In the case of PDE2, this regulation primarily involves the allosteric st...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.106.144501
更新日期:2007-06-08 00:00:00