INT175455
From wiki-pain
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Sentences Mentioned In
Key: | 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. | |||||||||||||||
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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 ? | |||||||||||||||
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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. | |||||||||||||||
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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. | |||||||||||||||
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The exact mechanism(s) by which GGA treatment increases HSPB8 expression in HSPB5 R120G TG mice has not been fully elucidated. | |||||||||||||||
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We then examined the long-term effects of GGA on small HSP expression in the NTG and HSPB5 R120G TG mice (Figure 2CE). | |||||||||||||||
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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). | |||||||||||||||
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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). | |||||||||||||||
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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). | |||||||||||||||
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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). | |||||||||||||||
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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 8AD). | |||||||||||||||
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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). | |||||||||||||||
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Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. | |||||||||||||||
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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). | |||||||||||||||
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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 5AG, Table 1). | |||||||||||||||
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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. | |||||||||||||||
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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). | |||||||||||||||
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Premature death was completely suppressed by the overexpression of HSPB8 in R120G TG mice (Figure 5G). | |||||||||||||||
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These results imply that the overexpression of HSPB8 is critical to suppress the progression of cardiac disease in HSPB5 R120G TG mice.
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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. | |||||||||||||||
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General Comments
This test has worked.