Abundance and Location of the Small Heat Shock Proteins HSP25 and αB-Crystallin in Rat and Human Heart

Lutsch, Gudrun; Vetter, Roland; Offhauss, Ulrike; Wieske, Martin; Gröne, Hermann Josef; Klemenz, Roman; Schimke, Ingolf; Stahl, Joachim; Benndorf, Rainer

doi:10.1161/01.cir.96.10.3466

Cited by 129 publications

(106 citation statements)

References 49 publications

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“…CryAB R120G shows enhanced binding to the protein FBX4, an F box protein that is an integral part of the ubiquitin protein isopeptide ligase complex Skp-Cullin-F box (SCF), and the mutated protein recruits this component effectively to an insoluble cellular fraction, with a subsequent effect on ubiquitination patterns (37). CryAB can also bind to actin (16) as well as titin (38), and the protein has been detected at the M-line, which is consistent with its interaction with myomesin-2 (39). By using the hsp20 domain as bait in yeast two-hybrid screens, we have isolated titin, TnI, myomesin, and myosin-binding protein C, and analyses in which the R120G-hsp20 domain was compared with the wild-type sequence showed that the mutant fragment displayed higher affinity for a subset of the sarcomeric proteins, as evidenced by an increased rate of growth for the transformed yeast colonies under highly selective conditions (A.S. and J.R., unpublished data).…”

Section: Discussionmentioning

confidence: 65%

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Sanbe

Osińska

Saffitz

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

271

321

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An R120G missense mutation in the small heat shock protein ␣-B-crystallin (CryAB R120G ) causes desmin-related cardiomyopathy (DRM). DRM is characterized by the formation of aggregates containing CryAB and desmin, and it can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. In this article, we show that expression of CryAB R120G leads to the formation of electron-dense bodies characteristic of the DRMs and identify these bodies as aggresomes, which are characteristic of the neurodegenerative diseases. Cardiomyocytes transfected with adenovirus containing CryAB R120G establish the necessity and sufficiency of CryAB R120G expression for aggresome formation. The commonality of these aggresomes with oligomeric protein aggregates found in the amyloid-related degenerative diseases was corroborated by the presence of high levels of amyloid oligomers that may represent a primary toxic species in the amyloid diseases. These oligomeric amyloid intermediates are present also in cardiomyocytes derived from many human dilated and hypertrophic cardiomyopathies.H uman heart failure is the leading cause of death in the developed world, and it represents a final common endpoint for several disease entities, including hypertension, coronary artery disease, and the cardiomyopathies (1, 2). A lack of pathogenic commonality is underscored by the large number of mutations in different classes of cardiac proteins that have been linked to dilated and hypertrophic cardiomyopathy (HCM) (3). Mutations in the cytoskeletal and associated proteins can be causative because these proteins function in structural, sensor, and signaling roles in the normal and diseased cardiomyocyte (4). For example, up-regulation of the intermediate filament protein desmin occurs in cardiac disorders such as cardiac hypertrophy and congestive heart failure (CHF) (5), and desmin mutations are associated with desmin-related cardiomyopathy (DRM) and idiopathic dilated cardiomyopathy (6, 7). Mutations in other proteins also have been associated with the DRMs, and genetic evidence linking an R120G mutation in ␣-B-crystallin (CryAB, CryAB R120G ) to human DRM (8) prompted a series of experiments in which we showed that cardiac-restricted transgenic (TG) expression of CryAB R120G was sufficient to cause heart failure in a mouse model (9). Although up-regulation of CryAB is associated with disease states including DRM, its synthesis probably represents a general cellular response to stress because CryAB has chaperone-like activity. Indeed, CryAB, which binds to both desmin and cytoplasmic actin, probably participates normally as a chaperone in intermediate filament formation and maintenance in the heart.The ␣-crystallins (␣-A and ␣-B) were of interest initially as major structural proteins present in the lens of the vertebrate eye. However, the discovery that they were related to the small heat shock proteins (hsps) in Drosophila (10) prompted reevaluation of their broader role(s), and it is now known that CryAB belongs to the sma...

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Section: Discussionmentioning

confidence: 65%

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Sanbe

Osińska

Saffitz

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

271

321

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“…The protective effect of B-crystallin on desmin is well supported by genetic evidence (Vicart et al, 1998;Wang et al, 2003). However, in stressed myocytes, HSP27 and B-crystallin can localize to the I-band region outside the Z-disk (Lutsch et al, 1997;Golenhofen et al, 1999Golenhofen et al, , 2002Golenhofen et al, , 2004Bullard et al, 2004) where desmin and -actinin are not present. Even though the two sHSPs interact with actin stress fibers, including cytoskeletal actin fibers in premature cardiomyocytes (Verschuure et al, 2002;Singh et al, 2007), it is not clear whether they associate with sarcomeric actin.…”

Section: Titin Spring Elements Act As Monomers In Vitromentioning

confidence: 92%

“…In response to potentially harmful insults, the myocyte sHSPs, including B-crystallin and HSP27, preferentially translocate from the cytosol to the myofibrils, where they bind to the sarcomeric Z-disk and/or I-band (Barbato et al, 1996;Lutsch et al, 1997;van de Klundert et al, 1998;Golenhofen et al, 1999;Fischer et al, 2002;Paulsen et al, 2009). Whether or not this translocation depends on the phosphorylation state of sHSPs is controversial (Mymrikov et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Human myocytes are protected from titin aggregation-induced stiffening by small heat shock proteins

Kötter¹,

Unger²,

Hamdani³

et al. 2014

J Gen Physiol

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“…Hsp27 comprises approximately 0.1% of the total protein content [12] in the adult heart and its expression is increased during both physiological and pathological hypertrophy [13]. This increase is thought to be cardioprotective since the constitutive activation of heat shock transcription factor 1, which leads to an increase in hsp27 expression, prevents cardiac dysfunction and hypertrophy during chronic pressure overload [13].…”

Section: Introductionmentioning

confidence: 99%

“…Chronic pressure overload [20], heart failure [12,21], ischemia [22], haemorrhagic shock [23], and oxidative stress [24,25] induce hsp27 phosphorylation in the heart. Furthermore, hsp27 phosphorylation plays an important role in heat-shock-induced prevention of doxorubicin cardiotoxicity [26,27] and is associated with improved recovery of function following ischemic injury [28].…”

Section: Introductionmentioning

confidence: 99%

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

et al. 2012

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Chronic hemodynamic overload results in left ventricular hypertrophy, fibroblast proliferation, and interstitial fibrosis. The small heat shock protein hsp27 has been shown to be cardioprotective and this requires a phosphorylatable form of this protein. To further understand the regulation of hsp27 in heart in response to stress, we investigated the ability of elevated aortic pressure to activate hsp27-kinase activities. Isolated hearts were subjected to retrograde perfusion and then snapfrozen. Hsp27-kinase activity was measured in vitro as hsp27 phosphorylation. Immune complex assays revealed that MK2 activity was low in non-perfused hearts and increased following crystalline perfusion at 60 or 120 mmHg. Hsp27-kinase activities were further studied following ion-exchange chromatography. Anion exchange chromatography on Mono Q revealed 2 peaks ('b' and 'c') of hsp27-kinase activity. A third peak 'a' was detected upon chromatography of the Mono Q flow-through fractions on the cation exchange resin, Mono S. The hsp27-kinase activity underlying peaks 'a' and 'c' increased as perfusion pressure was increased from 40 to 120 mmHg. In contrast, peak 'b' increased over pressures 60-100 mmHg but was decreased at 120 mmHg. Peaks 'a', 'b', and 'c' contained MK2 immunoreactivity, whereas MK3 and MK5 immunoreactivity was detected in peak 'a'. p38 MAPK and phospho-p38 MAPK were also detected in peaks 'b' and 'c' but absent from peak 'a'. Hsp27-kinase activity in peaks 'b' and 'c' (120 mmHg) eluted from a Superose 12 gel filtration column with an apparent molecular mass of 50-kDa. Hence, peaks 'b' and 'c' were not a result of MK2 forming complexes. In-gel hsp27-kinase assays revealed a single 49-kDa renaturable hsp27-kinase activity in peaks 'b' and 'c' at 60 mmHg, whereas several hsp27-kinases (p43, p49, p54, p66) were detected in peaks 'b' and 'c' from hearts perfused at 120 mmHg. Thus, multiple hsp27-kinases were activated in response to elevated aortic pressure in isolated, perfused rat hearts and hence may be implicated in regulating the cardioprotective effects of hsp27 and thus may represent targets for cardioprotective therapy.

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Abundance and Location of the Small Heat Shock Proteins HSP25 and αB-Crystallin in Rat and Human Heart

Cited by 129 publications

References 49 publications

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Human myocytes are protected from titin aggregation-induced stiffening by small heat shock proteins

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

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