INT175455

Context Info Confidence 0.76 First Reported 2003 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 54 Total Number 56 Disease Relevance 59.87 Pain Relevance 3.90

nucleus (Hspb8) intracellular (Hspb8) response to stress (Hspb8) cytoplasm (Hspb8)

Anatomy Link Frequency cardiomyocyte 3 apoptotic cell 2 B-cells 2 hearts 2 sputum 1 Hspb8 (Mus musculus)

Pain Link Frequency Relevance Heat Inflammation 600 99.90 Inflammatory response 53 99.44 cytokine 342 99.36 Inflammatory marker 6 98.32 dexamethasone 27 97.58 fibrosis 127 96.40 Central nervous system 25 94.92 tolerance 25 92.48 agonist 31 79.36 antagonist 25 74.56

Disease Link Frequency Relevance Heat Targeted Disruption 2423 100.00 Aspergillus Infection 225 100.00 Pulmonary Eosinophilia 5 99.92 INFLAMMATION 601 99.90 Nicotine Addiction 608 99.72 Apoptosis 134 99.64 Death 310 99.58 Rhinitis 75 99.50 Pneumonia 76 99.44 Asthma 1007 99.26

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Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

In the model tested here, we found that long-term treatment with GGA results in HSPB8 induction and a similar level of overexpression of HSPB8 via transgenic manipulation recapitulates the protective effect of GGA in HSPB5 R120G cardiomyopathy.

Gene_expression (overexpression) of HSPB8 associated with targeted disruption and coronary heart disease

1) Confidence 0.76 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 0.99 Pain Relevance 0

To clarify the functional role of HSPB8 induction on the development of HSPB5 R120G cardiomyopathy and test sufficiency, we generated a TG mouse, in which HSPB8 is overexpressed in a cardiac-specific manner using the inducible ?

Gene_expression (overexpressed) of HSPB8 associated with targeted disruption and coronary heart disease

2) Confidence 0.76 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.48 Pain Relevance 0.03

Cardiac-specific TG mice expressing HSPB8 also inhibit the progression of cardiomyopathy in the R120G TG mice, suggesting that the induction of HSPB8 may play a role in inhibiting the development of DRM.

Gene_expression (expressing) of HSPB8 associated with targeted disruption and coronary heart disease

3) Confidence 0.76 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.38 Pain Relevance 0.05

In the present study, we show that geranylgeranylacetone (GGA), a nontoxic antiulcer drug and inducer of small HSPs [16], can induce expression of HSPB8 and HSPB1 and reduce the formation of amyloid oligomers as well as insoluble aggregates in HSPB5 R120G TG mice.

Gene_expression (expression) of HSPB8 associated with targeted disruption and alzheimer's dementia

4) Confidence 0.76 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.43 Pain Relevance 0.04

The exact mechanism(s) by which GGA treatment increases HSPB8 expression in HSPB5 R120G TG mice has not been fully elucidated.

Gene_expression (expression) of HSPB8 associated with targeted disruption

5) Confidence 0.76 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.51 Pain Relevance 0.05

We then examined the long-term effects of GGA on small HSP expression in the NTG and HSPB5 R120G TG mice (Figure 2C–E).

Gene_expression (expression) of small HSP associated with targeted disruption

6) Confidence 0.76 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.55 Pain Relevance 0

The expression level of HSPB8 in tTA/HSPB8 double TG (tTA/HSPB8 TG) mice was twice the NTG level, while expression of the other HSPs tested was unchanged (Figure 5A and B).

Gene_expression (expression) of HSPB8 associated with targeted disruption

7) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.43 Pain Relevance 0.03

Although the expression levels of HSPB5 in the WT and R120G hearts were similar, HSPB8, HSPB1 and HSP70 were up-regulated in the hearts from R120G TG mice as compared with those of HSPB5 WT TG and NTG mice (Figure 2A and B).

Gene_expression (expression) of HSPB8 in hearts associated with targeted disruption

8) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.73 Pain Relevance 0

There were no differences in HSPB8, HSPB1 and HSP70 levels between WT TG and NTG mice, although HSPB5 was overexpressed in WT TG mice (Figure 2A and B).

Gene_expression (levels) of HSPB8 associated with targeted disruption

9) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.73 Pain Relevance 0

The expression level of HSPB8 in tTA/HSPB8 double TG (tTA/HSPB8 TG) mice was twice the NTG level, while expression of the other HSPs tested was unchanged (Figure 5A and B).

Gene_expression (expression) of HSPB8 associated with targeted disruption

10) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.46 Pain Relevance 0.03

Both GGA treatment and overexpression of HSPB8 resulted in inhibition of cytochrome c release from mitochondria, decreased activation of caspase-3 and attenuated TUNEL-positive cardiomyocyte death in R120G TG mice (Figure 8A–D).

Gene_expression (overexpression) of HSPB8 in cardiomyocyte associated with targeted disruption and death

11) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.83 Pain Relevance 0

While GGA increased the expression levels of HSPB8 and HSPB1 as well as HSP70 in a dose-dependent manner, no induction of HSPB5 was observed (Figure 1A and B).

Gene_expression (expression) of HSPB8

12) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 0.43 Pain Relevance 0

Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival.

Gene_expression (Overexpression) of HSPB8 associated with alzheimer's dementia

13) Confidence 0.59 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2670514 Disease Relevance 1.09 Pain Relevance 0.05

While GGA increased the expression levels of HSPB8 and HSPB1 as well as HSP70 in a dose-dependent manner, no induction of HSPB5 was observed (Figure 1A and B).

Gene_expression (levels) of HSPB8

14) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 0.43 Pain Relevance 0

No significant differences in cardiac function, heart weight, histology or survival rate could be detected in these mice, suggesting that twice the level of overexpression of HSPB8 is nontoxic for cardiomyocytes (Figure 5A–G, Table 1).

Gene_expression (overexpression) of HSPB8 in cardiomyocytes

15) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.56 Pain Relevance 0

In another set of experiments, we treated tTA/HSPB8/R120G triple TG mice from 4 weeks to 30 weeks of age with doxycycline to shut down HSPB8 transgene expression.

Gene_expression (expression) of HSPB8 associated with targeted disruption

16) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.96 Pain Relevance 0.04

The expression level of HSPB8 in hearts of R120G TG and tTA/HSPB8/R120G triple TG mice was 1.9- and 3.4-fold that of NTG mice, respectively, while the other small HSPs including HSPB5 were similar between the tTA/HSPB8/R120G triple TG mice and the R120G TG mice (Figure 5A and B).

Gene_expression (expression) of HSPB8 in hearts associated with targeted disruption

17) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.82 Pain Relevance 0.04

Premature death was completely suppressed by the overexpression of HSPB8 in R120G TG mice (Figure 5G).

Gene_expression (overexpression) of HSPB8 associated with targeted disruption and death

18) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.85 Pain Relevance 0.05

These results imply that the overexpression of HSPB8 is critical to suppress the progression of cardiac disease in HSPB5 R120G TG mice.

Gene_expression (overexpression) of HSPB8 associated with targeted disruption and heart disease

19) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 2.09 Pain Relevance 0.03

Next, we crossbred HSPB8 TG mice with R120G TG mice and generated tTA/HSPB8/R120G triple TG mice, which overexpress HSPB5 R120G and HSPB8 proteins in a cardiac-specific manner.

Gene_expression (overexpress) of HSPB8 associated with targeted disruption

20) Confidence 0.59 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2670514 Disease Relevance 1.79 Pain Relevance 0.03

General Comments

This test has worked.