Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits β-Agonist-Induced Cardiac Apoptosis

Fan, Guo-Chang; Chu, Guoxiang; Mitton, Bryan; Song, Qiujing; Yuan, Qunying; Kranias, Evangelia G.

doi:10.1161/01.res.0000129179.66631.00

Cited by 112 publications

(155 citation statements)

References 40 publications

(35 reference statements)

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…It has also been reported that acute expression of HSP20 in rat cardiomyocytes is protective against apoptosis (20). However, the exact mechanism of HSP20 underlying apoptosis of HCC remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein 20 (HSPB6) regulates apoptosis in human hepatocellular carcinoma cells: Direct association with Bax

et al. 2014

View full text Add to dashboard Cite

Abstract.A small heat shock protein (HSP), HSP20 (HSPB6) is ubiquitously expressed in various tissues and has several functions. We previously reported that the expression of HSP20 protein in human hepatocellular carcinoma (HCC) cells is inversely proportional to the progression of HCC. In addition, we showed that HSP20 is associated with phosphoinositide 3-kinase (PI3K) and inhibits the proliferation of HCC cells via suppression of the AKT signaling pathway. However, the relationship between HSP20 and apoptosis in HCC has not yet been elucidated. To clarify whether HSP20 is implicated in the apoptosis of HCC cells, in the present study, we examined the effect of HSP20 on caspases, the central regulators of apoptosis, using human HCC-derived HuH7 cells that are transfected with wild-type human HSP20 (HSP20-overexpressing cells). The cleavage of caspase-3 and caspase-7 in HSP20-overexpressing cells was enhanced compared with the empty vector-transfected cells (control cells). In addition, the cleavage of nuclear poly (ADP-ribose) polymerase (PARP) in HSP20-overexpressing cells was also strengthened. We further investigated the direct targets of HSP20 focusing on Bcl-2 family proteins in the HSP20-overexpressing cells. HSP20 proteins in the cells were coimmunoprecipitated with Bax. On the contrary, Bad, Bcl-2 and Bcl-xL were not coimmunoprecipitated with HSP20. These findings strongly suggest that HSP20 directly associates with Bax and stimulates caspase cascade in human HCC cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Heat shock protein 20 (HSPB6) regulates apoptosis in human hepatocellular carcinoma cells: Direct association with Bax

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[12][13][14] Overexpression of Hsp20 was associated with cardiac protection from ischemia/reperfusion-induced injury and reduced myocardial infarction-mediated apoptosis, 15 consistent with the protective effects of Hsps in the adaptive responses of the heart to physiological/pathophysiological stress. 16,17 Furthermore, adenoviral-mediated overexpression of Hsp20 in isolated adult rat cardiomyocytes revealed inhibition of ␤-adrenergic-induced apoptosis.…”

mentioning

confidence: 79%

“…16,17 Furthermore, adenoviral-mediated overexpression of Hsp20 in isolated adult rat cardiomyocytes revealed inhibition of ␤-adrenergic-induced apoptosis. 12 To determine whether Hsp20 may mediate an in vivo feedback mechanism by which ␤-adrenergic signaling regulates its own subcellular-axis, we used a transgenic (TG) mouse model with cardiac overexpression of Hsp20 and delineated the mechanisms underlying ␤-agonist-induced cardiac remodeling. Our findings indicate that increased sympathetic drive is associated with activation of the cardiac ASK1 cascade, leading to cardiac hypertrophy and heart failure, whereas increased Hsp20 expression attenuates cardiac remodeling and prevents further deterioration, apoptosis, and fibrosis, because of its downregulation of the ASK1-JNK/p38 pathway.…”

mentioning

confidence: 99%

Small Heat-Shock Protein Hsp20 Attenuates β-Agonist–Mediated Cardiac Remodeling Through Apoptosis Signal–Regulating Kinase 1

Fan

Yuan

Song

et al. 2006

Circulation Research

Self Cite

View full text Add to dashboard Cite

Abstract-Chronic stimulation of the ␤-adrenergic neurohormonal axis contributes to the progression of heart failure and mortality in animal models and human patients. In cardiomyocytes, activation of the ␤-adrenergic pathway has been shown to result in transiently increased expression of a cardiac small heat-shock protein Hsp20. The present study shows that cardiac overexpression (10-fold) of Hsp20 may protect the heart against ␤-agonist-induced cardiac remodeling, associated with isoproterenol (50 g/g per day) infusion for 14 days. Hsp20 attenuated the cardiac hypertrophic response, markedly reduced interstitial fibrosis, and decreased apoptosis. Contractility was also preserved in hearts with increased Hsp20 levels. These beneficial effects were associated with attenuation of the ASK1-JNK/p38 (apoptosis signal-regulating kinase 1/c-Jun NH 2 -terminal kinase/p38) signaling cascade triggered by isoproterenol, whereas there was no difference in either extracellular signal-related kinase 1/2 or Akt activation. Parallel in vitro experiments supported the inhibitory role of Hsp20 on enforced ASK1-JNK/p38 activation in both H9c2 cells and adult rat cardiomyocytes. Immunostaining studies also demonstrated that Hsp20 colocalizes with ASK1 in cardiomyocytes. Taken together, our findings indicate that (1) ␤-agonist-induced cardiac injury is associated with activation of the ASK1-JNK/p38 cascade; (2) increased expression of Hsp20 attenuates the induction of remodeling, dysfunction, and apoptosis in response to sustained ␤-adrenergic stimulation; and (3) A poptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK), which activates the c-Jun NH 2 -terminal kinase (JNK) (also known as stress-activated protein kinase [SAPK]) and p38 MAPK signaling cascades. 1 Overexpression of wild-type (WT) or constitutively active ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas rat neonatal ASK1-deficient cardiomyocytes were resistant to H 2 O 2 -induced apoptosis. 2 Recent studies have indicated that ablation of ASK1 was associated with (1) inhibition of angiotensin II-and G protein-coupled receptor (GPCR) agonist-induced heart dysfunction and dilatation 3,4 ; (2) attenuation of cardiac remodeling mediated by myocardial infarction and pressure overload 2 ; and (3) rescue of Raf-1 knockout-induced cardiac dysfunction and apoptosis. 5 These observations suggest that inhibition of ASK1 may be a promising target for prevention of cardiac remodeling and, thus, suppression of heart failure onset and progression.Heart failure is characterized by enhanced adrenergic stimulation to correct systolic and diastolic dysfunction, but chronic elevation of sympathetic drive can exert deleterious effects on the myocardium, promoting the development of fibrotic cardiomyopathy. 6,7 The mechanisms underlying the transition between the contractile benefits and the maladaptive processing, including cell death, are still heavily debated. 8,9 The MAPKs, mainly incl...

show abstract

“…Mitogen activated protein kinase activated protein (MAPKAP) kinase-2 is responsible for Hsp27 phosphorylation at all three sites [125,126]. In addition to Ac, Bc and Hsp27, phosphorylation is also common to other sHsps such as Hsp20 [127,128] and occurs readily in all tissues. Phosphorylation of Hsp20 occurs at Ser16 and is mediated by cyclic nucleotide-dependent protein kinases [129].…”

Section: Phosphorylationmentioning

confidence: 99%

Small heat-shock proteins: important players in regulating cellular proteostasis

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

View full text Add to dashboard Cite

Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of posttranslational modifications in sHsp chaperone function, particularly in the context of disease. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract (word count = 159)Small heat-shock proteins (sHsps) are a diverse family of intracellular molecular chaperone proteins that play a critical role in preventing protein unfolding, misfolding and aggregation, particularly under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) and thereby avoid the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. There has been much research into the structure and mechanism of chaperone action of sHsps over approximately the past 30 years, and significant progress has been made of late, however, there are still many unanswered questions relating to these aspects of sHsps. In this review, we outline some of the recent advances in understanding the structure and function of mammalian sHsps, particularly in the context of their many and varied roles in disease.

show abstract

Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits β-Agonist-Induced Cardiac Apoptosis

Cited by 112 publications

References 40 publications

Heat shock protein 20 (HSPB6) regulates apoptosis in human hepatocellular carcinoma cells: Direct association with Bax

Heat shock protein 20 (HSPB6) regulates apoptosis in human hepatocellular carcinoma cells: Direct association with Bax

Small Heat-Shock Protein Hsp20 Attenuates β-Agonist–Mediated Cardiac Remodeling Through Apoptosis Signal–Regulating Kinase 1

Small heat-shock proteins: important players in regulating cellular proteostasis

Contact Info

Product

Resources

About