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Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases.

Ngo J, Matsuyama M, Kim C, Poventud-Fuentes I, Bates A, Siedlak SL, Lee HG, Doughman YQ, Watanabe M, Liner A, Hoit B, Voelkel N, Gerson S, Hasty P, Matsuyama S - Cell Death Dis (2015)

Bottom Line: Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis.Importantly, Bax deficiency appeared to delay the development of emphysema.This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA [2] Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

ABSTRACT
Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(-/-) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax-mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70(-/-) mice. Here, we show that ku70(-/-) bax(+/-) and ku70(-/-) bax(-/-) mice have better survival, especially in females, than ku70(-/-) mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70- background. Moreover, we found that ku70(-/-) mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70(-/-) mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70(-/-) and Bax-deficient ku70(-/-) mice may be useful models to study these diseases.

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Bax deficiency improved the survival and extended the lifespan of Ku70- mice. Kaplan–Meier survival curves are shown for (a) all mice analyzed, (b) females, and (c) males. Sex-specific survival are shown for (d) ku70−/−, (e) ku70−/−bax+/−, and (f) ku70−/−bax−/−. (g) The table summarizes the median survival of all mice analyzed
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fig1: Bax deficiency improved the survival and extended the lifespan of Ku70- mice. Kaplan–Meier survival curves are shown for (a) all mice analyzed, (b) females, and (c) males. Sex-specific survival are shown for (d) ku70−/−, (e) ku70−/−bax+/−, and (f) ku70−/−bax−/−. (g) The table summarizes the median survival of all mice analyzed

Mentions: The ku70−/− mice in this study exhibited shortened lifespans as previously reported,6 with a median survival of 26 weeks (n=55). The ku70+/+ (wild type) mice in the same cohort had a survival rate of 99.4% (n=355) at 26 weeks of age (data not shown), and it has been reported that the median lifespan of wild-type mice (C57BL/6J) is ∼110 weeks.31 In comparison with ku70−/− mice, the median survival of ku70−/−bax+/− and ku70−/−bax−/− mice was significantly longer at 37.5 (n=46; P<0.001) and 38 (n=23; P<0.01) weeks, respectively (Figures 1a and g). The maximum lifespans of ku70−/−bax+/− (803 days, female) and ku70−/−bax−/− (951 days, female) mice were also greater than that of ku70−/− mice (656 days, female) (Figures 1a and b). These results suggest that Bax deficiency was able to decrease the mortality of ku70−/− mice that have been reported to develop premature aging phenotypes.2, 3, 4, 5, 6 The complete deletion of Bax may have a greater positive impact on the overall survival and lifespan of Ku70- mice based on the lower observed mortality of ku70−/−bax−/− mice compared with ku70−/−bax+/− mice after 30 weeks of age. The extended survival because of Bax deficiency was also much more apparent in females than males (Figures 1b and c). Although there were no sex-dependent differences in the lifespan of ku70−/− mice (Figure 1d), these differences became obvious in ku70−/−bax+/− and ku70−/−bax−/− mice (Figures 1e–g).


Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases.

Ngo J, Matsuyama M, Kim C, Poventud-Fuentes I, Bates A, Siedlak SL, Lee HG, Doughman YQ, Watanabe M, Liner A, Hoit B, Voelkel N, Gerson S, Hasty P, Matsuyama S - Cell Death Dis (2015)

Bax deficiency improved the survival and extended the lifespan of Ku70- mice. Kaplan–Meier survival curves are shown for (a) all mice analyzed, (b) females, and (c) males. Sex-specific survival are shown for (d) ku70−/−, (e) ku70−/−bax+/−, and (f) ku70−/−bax−/−. (g) The table summarizes the median survival of all mice analyzed
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385910&req=5

fig1: Bax deficiency improved the survival and extended the lifespan of Ku70- mice. Kaplan–Meier survival curves are shown for (a) all mice analyzed, (b) females, and (c) males. Sex-specific survival are shown for (d) ku70−/−, (e) ku70−/−bax+/−, and (f) ku70−/−bax−/−. (g) The table summarizes the median survival of all mice analyzed
Mentions: The ku70−/− mice in this study exhibited shortened lifespans as previously reported,6 with a median survival of 26 weeks (n=55). The ku70+/+ (wild type) mice in the same cohort had a survival rate of 99.4% (n=355) at 26 weeks of age (data not shown), and it has been reported that the median lifespan of wild-type mice (C57BL/6J) is ∼110 weeks.31 In comparison with ku70−/− mice, the median survival of ku70−/−bax+/− and ku70−/−bax−/− mice was significantly longer at 37.5 (n=46; P<0.001) and 38 (n=23; P<0.01) weeks, respectively (Figures 1a and g). The maximum lifespans of ku70−/−bax+/− (803 days, female) and ku70−/−bax−/− (951 days, female) mice were also greater than that of ku70−/− mice (656 days, female) (Figures 1a and b). These results suggest that Bax deficiency was able to decrease the mortality of ku70−/− mice that have been reported to develop premature aging phenotypes.2, 3, 4, 5, 6 The complete deletion of Bax may have a greater positive impact on the overall survival and lifespan of Ku70- mice based on the lower observed mortality of ku70−/−bax−/− mice compared with ku70−/−bax+/− mice after 30 weeks of age. The extended survival because of Bax deficiency was also much more apparent in females than males (Figures 1b and c). Although there were no sex-dependent differences in the lifespan of ku70−/− mice (Figure 1d), these differences became obvious in ku70−/−bax+/− and ku70−/−bax−/− mice (Figures 1e–g).

Bottom Line: Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis.Importantly, Bax deficiency appeared to delay the development of emphysema.This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA [2] Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

ABSTRACT
Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(-/-) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax-mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70(-/-) mice. Here, we show that ku70(-/-) bax(+/-) and ku70(-/-) bax(-/-) mice have better survival, especially in females, than ku70(-/-) mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70- background. Moreover, we found that ku70(-/-) mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70(-/-) mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70(-/-) and Bax-deficient ku70(-/-) mice may be useful models to study these diseases.

Show MeSH
Related in: MedlinePlus