Hsp10 and Hsp60 Suppress Ubiquitination of Insulin-like Growth Factor-1 Receptor and Augment Insulin-like Growth Factor-1 Receptor Signaling in Cardiac Muscle

We have investigated the effects of two heat shock proteins, Hsp10 and Hsp60, on insulin-like growth factor-1 receptor (IGF-1R) signaling in cardiac muscle cells. Neonatal cardiomyocytes were transduced with Hsp10 or Hsp60 via adenoviral vector. Compared with the cells transduced with a control vector, overexpression of Hsp10 or Hsp60 increased the abundance of IGF-1R and IGF-1-stimulated receptor autophosphorylation. Thus, Hsp10 and Hsp60 overexpression increased the number of functioning receptors and amplified activation of IGF-1R signaling. IGF-1 stimulation of MEK, Erk, p90Rsk, and Akt were accordingly augmented. Transducing cardiomyocytes with antisense Hsp60 oligonucleotides reduced Hsp60 expression, decreased the abundance of IGF-1R, attenuated IGF-1R autophosphorylation, and suppressed the pro-survival action of IGF-1 in cardiomyocytes. Using cycloheximide to inhibit protein synthesis did not alter the effect of Hsp60 on IGF-1R signaling, and IGF-1R mRNA levels were not up-regulated by Hsp10 or Hsp60. Additional experiments showed that Hsp10 and Hsp60 suppressed polyubiquitination of IGF-1 receptor. These data indicate that Hsp10 and Hsp60 can modulate IGF-1R signaling through post-translational modification. In animal models of diabetes, diabetic myocardium is associated with decreased abundance of Hsp60, increased ubiquitination of IGF-1R, and lower level of IGF-1R protein. Declined myocardial protection is a major feature of diabetic cardiomyopathy. These data suggest that decreased Hsp60 expression and subsequent decline of IGF-1R signaling may be a fundamental mechanism underlying the development of diabetic cardiomyopathy. We have investigated the effects of two heat shock proteins, Hsp10 and Hsp60, on insulin-like growth factor-1 receptor (IGF-1R) signaling in cardiac muscle cells. Neonatal cardiomyocytes were transduced with Hsp10 or Hsp60 via adenoviral vector. Compared with the cells transduced with a control vector, overexpression of Hsp10 or Hsp60 increased the abundance of IGF-1R and IGF-1-stimulated receptor autophosphorylation. Thus, Hsp10 and Hsp60 overexpression increased the number of functioning receptors and amplified activation of IGF-1R signaling. IGF-1 stimulation of MEK, Erk, p90Rsk, and Akt were accordingly augmented. Transducing cardiomyocytes with antisense Hsp60 oligonucleotides reduced Hsp60 expression, decreased the abundance of IGF-1R, attenuated IGF-1R autophosphorylation, and suppressed the pro-survival action of IGF-1 in cardiomyocytes. Using cycloheximide to inhibit protein synthesis did not alter the effect of Hsp60 on IGF-1R signaling, and IGF-1R mRNA levels were not up-regulated by Hsp10 or Hsp60. Additional experiments showed that Hsp10 and Hsp60 suppressed polyubiquitination of IGF-1 receptor. These data indicate that Hsp10 and Hsp60 can modulate IGF-1R signaling through post-translational modification. In animal models of diabetes, diabetic myocardium is associated with decreased abundance of Hsp60, increased ubiquitination of IGF-1R, and lower level of IGF-1R protein. Declined myocardial protection is a major feature of diabetic cardiomyopathy. These data suggest that decreased Hsp60 expression and subsequent decline of IGF-1R signaling may be a fundamental mechanism underlying the development of diabetic cardiomyopathy. The insulin-like growth factor 1 (IGF-1) 1The abbreviations used are: IGF-1, insulin-like growth factor-1; IGF-1R, IGF-1 receptor; Erk, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MAP, mitogen-activated protein; DIG, digoxigenin; STZ, streptozotocin; ZDF, Zucker diabetic fatty; Ad, adenovirus; AS, antisense; SCR, scrambled oligo; DM, diabetes mellitus.1The abbreviations used are: IGF-1, insulin-like growth factor-1; IGF-1R, IGF-1 receptor; Erk, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MAP, mitogen-activated protein; DIG, digoxigenin; STZ, streptozotocin; ZDF, Zucker diabetic fatty; Ad, adenovirus; AS, antisense; SCR, scrambled oligo; DM, diabetes mellitus. binds to the IGF-1 receptor, induces autophosphorylation of the receptor, activates receptor tyrosine kinase, and triggers cascades of intracellular signaling events. IGF-1 receptor signaling is involved in the regulation of multiple aspects of biological actions (1LeRoith D. Werner H. Beitner-Johnson D. Roberts Jr., C.T. Endocr. Rev. 1995; 16: 143-163Crossref PubMed Scopus (1234) Google Scholar). For example, IGF-1 activation of phosphatidylinositol 3 kinase and MAP kinase suppresses cardiac muscle apoptosis and enhances myocardial protection during myocardial injuries (2Wu W. Lee W-L. Wu Y.Y. Chen D. Liu T-J. Jang A. Sharma P.M. Wang P.H. J. Biol. Chem. 2000; 275: 40113-40119Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 3Parrizas M. Saltiel A.R. LeRoith D. J. Biol. Chem. 1997; 272: 154-161Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar). In addition to phosphorylation and dephosphorylation, growth factor receptor signaling can be modulated through transcriptional and post-translational modification of ligands, receptors, and signaling intermediates. Recent studies (4Dalle S. Imamura T. Rose D.W. Worrall D.S. Ugi S. Hupfeld C.J. Olefsky J.M. Mol. Cell. Biol. 2002; 22: 6272-6285Crossref PubMed Scopus (72) Google Scholar, 5Rui L. Fisher T.L. Thomas J. White M.F. J. Biol. Chem. 2001; 276: 40362-40367Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar) have shown that insulin and IGF-1 receptor signaling can be modulated through post-translational modification of signaling molecules such as arrestin-1 and insulin receptor substrate (IRS2). There was evidence suggested that IGF-1 receptor signaling might be modulated through degradation of receptor proteins as proteolysis inhibitors prevented degradation of IGF-1 receptor (6Sepp-Lorenzino L. Ma Z. Lebwohl D.E. Vinitsky A. Rosen N. J. Biol. Chem. 1995; 270: 16580-16587Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). However, whether post-translational modification of IGF-1 receptor contributed to the regulation of IGF-1 receptor signaling in cardiac muscle has not yet been investigated. Heat shock proteins are a group of molecular chaperones that are capable of preventing protein damages and proteolysis. In cardiac muscle, Hsp60 and Hsp10 may form mitochondrial chaperoning complexes and are believed to play a role in the maintenance of normal mitochondria function (7Lau S. Patnaik N. Sayen M.R. Mestril R. Circulation. 1997; 96: 2287-2294Crossref PubMed Scopus (100) Google Scholar). Hsp60 and Hsp10 also exist in the cytosolic compartment and interact with cytosolic proteins (8Kirchhoff S.R. Gupta S. Knowlton A.A. Circulation. 2002; 105: 2899-2904Crossref PubMed Scopus (243) Google Scholar), which suggests that Hsp60 and Hsp10 may regulate proteins through post-translational modification. Whether Hsp10 and Hsp60 can modulate IGF-1 receptor signaling has not been studied. This study was carried out to determine whether Hsp10 and Hsp60 can modulate IGF-1 receptor signaling in cardiomyocytes. The results showed that IGF-1 receptor signaling can be modulated by Hsp60 and Hsp10 through post-translational modification in cardiac muscle cells. Further experiments on animal models of diabetes showed that the changes of Hsp60 paralleled the levels of IGF-1 receptor in various tissues. Moreover, diabetic myocardium exhibited reduced Hsp60 and increased ubiquitination of IGF-1 receptor. These findings may have significant implications in understanding the fundamental mechanisms that lead to a decreased myocardial protection during the development of diabetic cardiomyopathy. Materials—Mouse anti-Hsp60 monoclonal antibody and rabbit anti-Cpn10 (Hsp10) peptide polyclonal antibody were purchased from StressGen Biotechnologies Corp. (Victoria, British Columbia, Canada). Horseradish peroxidase-conjugated secondary antibodies to mouse and goat immunoglobulins were purchased from Jackson ImmunoResearch Laboratories (West Grove, PA). Other antibodies were from Santa Cruz Biolabs (Santa Cruz, CA). Immobilon-P membranes were from Millipore Co. (Bedford, MA). DIG RNA labeling kit, Anti-digoxigenin-AP antibodies, DNase I, protector RNase inhibitor, β-actin RNA probe, DIG Easy Hyb, Wash and Block Buffer Set, and positively charged nylon membranes were from Roche. A ≅0.71 kb fragment of IGF-1R cDNA (EcoRI insert from ATCC clone pIGF-1R.8, subcloned into pGEM-7Zf) was kindly provided by Dr. Murray Korc (University of California, Irvine, CA). Other chemicals were purchased from Sigma or Fisher Scientific. Animal Models of Diabetes—Two different models of diabetes were used in this study. Streptozotocin (STZ)-induced diabetes was obtained by injecting STZ (75 mg/kg body weight, intravenous) to 5-week-old Sprague-Dawley rats. Zucker Fatty rats (ZDF fa/fa) and lean control rats were obtained from Charles River Laboratories (9Phillips M.S. Liu Q. Hammond H. Dugan V. Hey P. Caskey C.T. Hess J.F. Nat. Genet. 1996; 13: 18-19Crossref PubMed Scopus (745) Google Scholar). Blood glucose levels were monitored by tail vein sampling, the diabetic rats were harvested 10 days after the onset of diabetes (random glucose > 200 mg/dL). The animal experimental protocol was approved by the IACUC at University of California, Irvine. Cell Culture and Transduction of Adenoviral Constructs—Primary cultures of neonatal cardiomyocytes were prepared from Sprague-Dawley rats according to a protocol we previously described (2Wu W. Lee W-L. Wu Y.Y. Chen D. Liu T-J. Jang A. Sharma P.M. Wang P.H. J. Biol. Chem. 2000; 275: 40113-40119Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). The construction of recombinant adenoviruses expressing Hsp10, Hsp60, and the control adenovirus Ad-SR was described previously (7Lau S. Patnaik N. Sayen M.R. Mestril R. Circulation. 1997; 96: 2287-2294Crossref PubMed Scopus (100) Google Scholar, 10Lin K.M. Lin B. Lian I.Y. Mestril R. Scheffler I.E. Dillmann W.H. Circulation. 2001; 103: 1787-1792Crossref PubMed Scopus (239) Google Scholar). In brief, the human HSP60 and HSP10 genes were cloned into the multiple cloning site of the adenoviral shuttle plasmid pACCMVpLpASR. The viruses were replicated in 293 cells, purified by Virakit™ from Virapau (Carlsbad, CA), and the viral titers were determined by plaque assay in 293 cells. Cardiomyocytes were plated in 100-mm Petri dishes in high glucose Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and 1% penicillin/streptomycin. When indicated, the cells were infected with adenoviruses of Ad-SR, Ad-Hsp10, or Ad-Hsp60 and incubated for 36–48 h at 37 °C, 5% CO2. Cell Viability—Cell viability was performed by staining the cells with calcein AM (Molecular Probe, Eugene, OR) as previously described (2Wu W. Lee W-L. Wu Y.Y. Chen D. Liu T-J. Jang A. Sharma P.M. Wang P.H. J. Biol. Chem. 2000; 275: 40113-40119Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Calcein AM hydrolyzes to calcein and retains only in live cells, thus serves as an indicator for cell viability. To measure cell viability, cardiomyocytes were plated in 48-well plates. After rinsing twice with 1× PBS buffer (pH 7.4), 200 μl of 1 μm calcein AM (in 1× PBS) were added to each well and incubated for 45 min at room temperature in the dark. The plates were analyzed with the Cytofluor 2300 Fluorescence Measurement System (Millipore) at excitation of 485 nm and emission of 530 nm. Western Blot—Cardiomyocytes were infected with Ad-SR (control cells), Ad-Hsp10, or Ad-Hsp60 for 48h and incubated in serum-free medium overnight. The cells were treated with IGF-1 or vehicles when indicated. Then the cells were lysed with lysis buffer (137 mm NaCl, 20 mm Tris-HCl, pH 7.5, 10% glycerol, 1% Triton X-100, 0.5% Nonidet P-40, 2 mm EDTA, pH 8.0, 3 μg/ml aprotinin, 3 μg/ml leupeptin, 2 mm phenylmethylsulfonyl fluoride, 20 mm NaF, 10 mm NaPP, and 2 mm Na3VO4). Equal amounts of proteins from each sample were separated by SDS-PAGE and then transferred to polyvinylidene difluoride membrane and incubated with a blocking buffer (5% nonfat milk in 20 mm Tris-HCl, pH 7.5, 137 mm NaCl, 0.1% Tween 20) for 1 h at room temperature. The membranes were sequentially incubated with primary antibodies overnight at 4 °C, washed three times (20 mm Tris-HCl, pH 7.5, 137 mm NaCl, and 0. 1% Tween 20), incubated with horseradish peroxidase-conjugated secondary antibodies (1:5000 dilution) for 1 h at room temperature, washed three times, and then detected with ECL (Amersham Biosciences). Immunoprecipitation—Immunoprecipitation was carried out as we previously reported (8Kirchhoff S.R. Gupta S. Knowlton A.A. Circulation. 2002; 105: 2899-2904Crossref PubMed Scopus (243) Google Scholar). The cells were lysed and the lysates (500 μg proteins in 1 ml) were pre-absorbed with 20 μl protein A/G agarose beads (Santa Cruz Biotechnology) at 4 °C for 30 min on a rocking platform, spun for 5 min at 10,000 rpm for 10 s, and the supernatant was incubated with specific primary antibody at 4 °C overnight. After incubation with 20 μl protein A/G agarose beads for 1.5 h at 4 °C, the immunocomplexes were collected by centrifugation and washed three times with ice-cold washing buffer (137 mm NaCl, 20 mm Tris-HCl, pH 7.5; 1% Triton X-100, 2 mm EDTA, pH 8.0; 2 mm PMSF, and 2 mm Na3VO4). The final products were briefly boiled and resolved with SDS-PAGE, and immunoblotted with specific antibodies as indicated. Northern Blot Analysis—Total RNAs were isolated with TRIzol reagent (Invitrogen). The quality of RNA was verified by electrophoresis with 1% agarose gel containing Northern were performed with a according to the In brief, amounts of RNA were resolved with 1% agarose gel and nylon IGF-1 receptor RNA were with by in in the of was performed at °C overnight in DIG Easy containing RNA After the membranes were washed two times in 0.1% for 10 min at room temperature and two times in 0.1% at °C for were sequentially incubated with a blocking for 30 antibodies with for 30 min at room temperature, and twice in the washing buffer min After for 5 min in the the were with the and to β-actin were used as control in Hsp60 with Hsp60 antisense oligonucleotides were to cardiomyocytes to the expression of Hsp60. oligonucleotides were obtained from CA). The antisense Hsp60 to to of Hsp60 and a scrambled was used as a control as previously described (8Kirchhoff S.R. Gupta S. Knowlton A.A. Circulation. 2002; 105: 2899-2904Crossref PubMed Scopus (243) Google Scholar). Cardiomyocytes were incubated with or in serum-free medium for data were as on data from three to The of from Western and Northern were with and The was by or of with when A was IGF-1 in the Cardiomyocytes Hsp10 or Hsp60 Hsp10 or Hsp60 can modulate IGF-1 receptor signaling, overexpression of Hsp10, and Hsp60 IGF-1 receptor autophosphorylation. To this neonatal cardiomyocytes were transduced with adenoviral Hsp10 or Hsp60. shown in the abundance of Hsp10 and Hsp60 increased Hsp10, in the cardiomyocytes infected with and of IGF-1 receptor was accordingly in the cardiomyocytes transduced with Hsp10 or Hsp60 with receptor antibodies showed that the abundance of IGF-1 receptor protein was increased in the cells Hsp10 or Hsp60 Further on receptor phosphorylation showed an increased of protein in the cells Hsp10 or Hsp60 or Ad-Hsp60 which suggests were functioning IGF-1 receptor in to IGF-1 activation In the effect of Hsp60 the effect of Hsp10 Further experiments showed that IGF-1-stimulated phosphorylation of MEK, Erk, and were accordingly increased in the cells Hsp10 or Hsp60 The effect of Hsp10 and Hsp60 on IGF-1 signaling at as well as of IGF-1 The effects of Hsp60 and Hsp10 on signaling were significant at of of IGF-1 the effect of Hsp10 and Hsp60 were at of IGF-1, phosphorylation of Akt were phosphorylation of and in the cells Hsp60. The of Hsp10 and Hsp60 of IGF-1 determine whether the effect of Hsp10 and Hsp60 on IGF-1 receptor increased synthesis IGF-1 receptor, cycloheximide or vehicles were added to the medium in the cells Hsp10 or Hsp60 In cells, cycloheximide reduced the abundance of IGF-1 receptor; the of IGF-1R in the cells treated with cycloheximide was the as in the However, the level of IGF-1 receptor in the cells Hsp10 or Hsp60. This suggests that the effect of Hsp10 and Hsp60 on IGF-1 receptor did not protein To that Hsp10 or Hsp60 did not IGF-1 receptor we analyzed the abundance of IGF-1 receptor mRNA with Northern The results showed that IGF-1 receptor mRNA level was not up-regulated by Hsp10 or Hsp60. These data evidence that Hsp10 and Hsp60 might have modulated the abundance of IGF-1 receptor through post-translational modification. can be through ubiquitination of To whether Hsp10 and Hsp60 can regulate ubiquitination of IGF-1 receptor, we analyzed the abundance of IGF-1 receptor shown in the abundance of IGF-1 receptor was reduced in the cells transduced with Hsp10 and Hsp60. The IGF-1 receptors and that receptors were Thus, the effect of Hsp10 and Hsp60 on IGF-1 receptor degradation might have involved of IGF-1 receptor In with the effect of Hsp10 and Hsp60 on IGF-1 receptor signaling, the effect of Hsp60 on receptor ubiquitination is the effect of These findings suggest that the effect of Hsp10 and Hsp60 on IGF-1 receptor signaling post-translational modification of receptor. Hsp60 IGF-1 Hsp60 a major role in the of IGF-1 receptor signaling in cardiac muscle, reduced expression of Hsp60 lead to a in IGF-1 receptor protein and receptor signaling. To this an antisense Hsp60 was to the cardiomyocytes to Hsp60 expression as shown in The control did not the expression of Hsp60. The of Hsp60 was by a of IGF-1 receptor protein in the cells with antisense Hsp60. Using this we have the abundance of IGF-1 receptor protein and receptor tyrosine phosphorylation in the control and IGF-1-stimulated cardiomyocytes IGF-1-stimulated receptor tyrosine phosphorylation was reduced in the cells with antisense Hsp60, and was by decreased activation of MEK, Erk, and Thus, Hsp60 expression lead to of IGF-1 receptor signaling. To determine whether of Hsp60 attenuated action of IGF-1, cardiomyocytes were to serum in the or of IGF-1 reduced cell in the cardiomyocytes. IGF-1 cardiomyocytes from the effect of serum in the cells and the cells. However, the pro-survival effect of IGF-1 was in the cells with the antisense Hsp60. The of Hsp60 and IGF-1 in findings thus suggest that Hsp60 is involved in the regulation of IGF-1 receptor signaling in cardiac muscle cells. IGF-1 signaling enhances myocardial Hsp60 may modulate myocardial through of IGF-1 receptor signaling. feature of diabetic is decreased myocardial protection myocardial To whether the of diabetes lead to of Hsp60 and IGF-1 receptor, we analyzed the abundance of myocardial Hsp60 and IGF-1 receptor protein in diabetes The abundance of Hsp60 and IGF-1 receptor was reduced in the In the abundance of insulin receptor was up-regulated as P.H. A. PubMed Scopus Google Scholar). In addition to Hsp60, we also investigated Hsp10 in the normal and diabetic the levels of myocardial Hsp10 were and not be detected with To the changes of Hsp60 and IGF-1 receptor in diabetic we the rats and the lean The levels of Hsp60 and IGF-1 receptor protein were reduced in the myocardium and The of Hsp60 and IGF-1 receptor proteins were decreased in the myocardium and Hsp60 and IGF-1 receptor were in the Hsp60 and IGF-1 receptor were increased in the These that Hsp60 the abundance of IGF-1 receptor. the of myocardial IGF-1 receptor in diabetic myocardium post-translational ubiquitination of IGF-1 receptor have increased in the diabetic To this we have analyzed ubiquitination of IGF-1 receptor in the shown in was increased polyubiquitination of IGF-1 receptor in the diabetic These suggest that the mechanisms underlying the of IGF-1 receptor in diabetic myocardium may of Hsp60 and subsequent in post-translational modification. IGF-1 an role in myocardial protection and P.H. 2001; PubMed Scopus Google Scholar). The biological actions of IGF-1 are through activation of IGF-1 receptors on cell studies (1LeRoith D. Werner H. Beitner-Johnson D. Roberts Jr., C.T. Endocr. Rev. 1995; 16: 143-163Crossref PubMed Scopus (1234) Google Scholar, R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D. 2002; PubMed Scopus Google Scholar) have shown that IGF-1 receptor signaling can be modulated in a number of such as increased synthesis of IGF-1 receptors, of receptors, different IGF-1 receptor and IGF-1 receptors and secondary In this study we have Hsp10 and Hsp60 as of IGF-1 receptor signaling in cardiac This is the that of the heat shock protein can IGF-1 receptor signaling in cardiac muscle cells through post-translational modification of the receptor. There are in the role of heat shock proteins in cardiac muscle D.S. 2001; PubMed Scopus Google Scholar). Heat shock proteins were as a of proteins by temperature A of biological actions of heat shock proteins have been such as protein protein and the two studies showed function of Hsp60 in the (7Lau S. Patnaik N. Sayen M.R. Mestril R. Circulation. 1997; 96: 2287-2294Crossref PubMed Scopus (100) Google Scholar, S. Knowlton A.A. Circulation. 2002; PubMed Scopus Google Scholar, J. P. A. B. 2002; PubMed Scopus Google Scholar). The expression of myocardial Hsp60 is increased J. P. A. B. 2002; PubMed Scopus Google Scholar), and overexpression of Hsp60 lead to of apoptosis in the cardiomyocytes and injuries K.M. Lin B. Lian I.Y. Mestril R. Scheffler I.E. Dillmann W.H. Circulation. 2001; 103: 1787-1792Crossref PubMed Scopus (239) Google Scholar). These with studies showed role of Hsp60 in cardiac muscle H. A. H. H. S. T. Mol. 2001; PubMed Scopus Google Scholar), the effect of Hsp60. The study showed a the abundance of Hsp60 and the of IGF-1 receptor signaling, which suggests the pro-survival action of Hsp60 may of IGF-1 receptor signaling. Hsp10 and Hsp60 modulated IGF-1 receptor signaling, the effects of Hsp10 were that of Hsp60. the abundance of myocardial Hsp10 is and be detected with Western in the two of rats we not Thus, two heat shock proteins, that Hsp60 is the major of IGF-1 receptor signaling in evidence suggest that heat shock proteins are involved in the regulation of intracellular signaling. chaperones signaling at membrane and during the of cytosolic signaling complexes M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). also chaperones receptor, and 1997; PubMed Scopus Google Scholar, B. P. Rosen N. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Rosen N. 2002; PubMed Scopus Google Scholar). The role of Hsp60 on intracellular signaling is Hsp60 was as a protein associated with and is involved in the activation of in cells L. Roberts 2002; Google Scholar). shown in the Hsp60 intracellular signaling at signaling heat shock proteins, such as are for effect on protein ubiquitination and protein (6Sepp-Lorenzino L. Ma Z. Lebwohl D.E. Vinitsky A. Rosen N. J. Biol. Chem. 1995; 270: 16580-16587Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar) shown that inhibitors of the can degradation of IGF-1 receptor, which suggests ubiquitination of IGF-1 receptor play a major role in the regulation of IGF-1 receptor myocardium is different from of the expression of Hsp60. Hsp60 expression is increased during a myocardial mechanism J. P. A. B. 2002; PubMed Scopus Google Scholar). we have that Hsp60 expression was reduced in diabetic of myocardial Hsp60 and implications in the of diabetic have not been investigated The changes of myocardial Hsp60 and IGF-1 receptor were in 1 and 2 which of Hsp60 and IGF-1 receptor is a feature of diabetic These findings evidence that reduced Hsp60 proteins may to an of IGF-1 receptor ubiquitination and subsequent decline in the number of IGF-1 receptor in diabetic Using antisense results showed that the pro-survival effect of IGF-1 was suppressed when Hsp60 was decreased and IGF-1 signaling IGF-1 receptor signaling myocardium from injuries through of of cardiac muscle of and of genes (2Wu W. Lee W-L. Wu Y.Y. Chen D. Liu T-J. Jang A. Sharma P.M. Wang P.H. J. Biol. Chem. 2000; 275: 40113-40119Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 3Parrizas M. Saltiel A.R. LeRoith D. J. Biol. Chem. 1997; 272: 154-161Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, Q. B. Wang A. Liu J. R. P. J. 1997; PubMed Scopus Google Scholar). IGF-1 receptor abundance can lead to decreased myocardial protection during myocardial and thus may play a fundamental role during the development of diabetic cardiomyopathy. data not only the that of receptor a to the development of diabetic also and that of IGF-1 signaling lead to myocardial protection in diabetic A. M. and P. Scholar). Further into the mechanisms for the effect of Hsp10 Hsp60 on ubiquitination of cardiac IGF-1 receptor may to for diabetic cardiomyopathy. We Dr. M. Korc for IGF-1R

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