THE ROLE OF HEAT SHOCK FACTOR-1 IN LPS MEDIATED CARDIAC CONTRACTILE FUNCTION.

Junctin (JCN) and triadin (TRD) share similar structures and they both function to anchor calsequestrin (CSQ) to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR) quaternary Ca-release complex. In failing human hearts, JCN and TRD protein levels are markedly decreased, implicating alterations in SR Ca-cycling and contractility. To address the role of combined JCN and TRD down-regulation in cardiac function, we generated and characterized a murine model deficient in both JCN and TRD. The double-knockout (DKO) mice presented lower body weight, poor fertility, and an apparent cardiac hypertrophy. In addition, deficiency of both JCN/TRD was associated with decreased peak Ca transient amplitude (34%), prolonged transient decay time (48%) and reduced caffeine-induced SR Ca-release. This depressed contractility was also confirmed at the intact organ (Langendorff perfusion) and whole animal (by echocardiography and catheterization) levels. Furthermore, examination of the properties of Ca sparks, which are informative of ryanodine receptor (RyR) gating , revealed increased frequency in the DKO myocytes, which indicated a larger opening probability of RyR. These findings suggest that the combined JCN/TRD-deficiency is associated with leaky RyR and depressed cardiac Ca-cycling, which may contribute to the progression of heart failure. This research has received full or partial funding support from the American Heart Association, AHA National Center. Table 1. Hemodynamic parameters from echocardiography and catheterization

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Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas

Journal of Gastroenterology and Hepatology ◽

10.1111/jgh.14078 ◽

2018 ◽

Vol 33 (7) ◽

pp. 1407-1412

Author(s):

Yoichiro Kawashita ◽

Yuji Morine ◽

Yu Saito ◽

Chie Takasu ◽

Tetsuya Ikemoto ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Intrahepatic Cholangiocarcinomas

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Poly(ADP-ribosyl)ation regulates heat shock factor-1 activity and the heat shock response in murine fibroblasts

Biochemistry and Cell Biology ◽

10.1139/o06-083 ◽

2006 ◽

Vol 84 (5) ◽

pp. 703-712 ◽

Cited By ~ 14

Author(s):

Silvia Fossati ◽

Laura Formentini ◽

Zhao-Qi Wang ◽

Flavio Moroni ◽

Alberto Chiarugi

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Heat Shock Factor ◽

Binding Motif ◽

Heat Shock Factor 1 ◽

Shock Response ◽

Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1−/− than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP–27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1−/− than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-κB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

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Role of heat shock factor-1 activation in the doxorubicin-induced heart failure in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01047.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. H1832-H1841 ◽

Cited By ~ 39

Author(s):

Kaushik Vedam ◽

Yoshinori Nishijima ◽

Lawrence J. Druhan ◽

Mahmood Khan ◽

Nicanor I. Moldovan ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Heat Shock ◽

Mrna Level ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Knock Out ◽

Apoptotic Protein ◽

Shock Proteins

Treating cancer patients with chemotherapeutics, such as doxorubicin (Dox), cause dilated cardiomyopathy and congestive heart failure because of oxidative stress. On the other hand, heat shock factor-1 (HSF-1), a transcription factor for heat shock proteins (Hsps), is also known to be activated in response to oxidative stress. However, the possible role of HSF-1 activation and the resultant Hsp25 in chemotherapeutic-induced heart failure has not been investigated. Using HSF-1 wild-type (HSF-1+/+) and knock-out (HSF-1−/−) mice, we tested the hypothesis that activation of HSF-1 plays a role in the development of Dox-induced heart failure. Higher levels of Hsp25 and its phosphorylated forms were found in the failing hearts of Dox-treated HSF-1+/+ mice. More than twofold increase in Hsp25 mRNA level was found in Dox-treated hearts. Proteomic analysis showed that there is accumulation and aggregation of Hsp25 in Dox-treated failing hearts. Additionally, Hsp25 was found to coimmunoprecipitate with p53 and vice versa. Further studies indicated that the Dox-induced higher levels of Hsp25 transactivated p53 leading to higher levels of the pro-apoptotic protein Bax, but other p53-related proteins remained unaltered. Moreover, HSF-1−/− mice showed significantly reduced Dox-induced heart failure and higher survival rate, and there was no change in Bax upon treating with Dox in HSF-1−/− mice. From these results we propose a novel mechanism for Dox-induced heart failure: increased expression of Hsp25 because of oxidant-induced activation of HSF-1 transactivates p53 to increase Bax levels, which leads to heart failure.

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