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

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-null 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.

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

“…Ku70 and Bax were found to interact in the cytoplasm and to inhibit Bax activation [20,64,115,117]. Upon Ku70 knockdown or acetylation, Bax dissociates from the Ku70 complex and translocates to the mitochondria [16,117,118,119]. Overexpression of Ku70 blocks apoptotic cell death induced by transfected Bax [120].…”

Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax

“…Bax knockout mice show a significant increase of the brain size and weight due to the increased survival of neurons during development. [31][32][33] However, the mutant mouse does not develop other major abnormalities except defects in spermatogenesis and an extended female reproductive period. 31,32 This phenotype suggests that Bax plays a nonreplaceable role in the nervous system as an inducer of programed cell death.…”

“…Ku70 KO mouse), Bax gene knockout resulted in the development of pulmonary hypertension-like diseases due to the abnormally increased number of endothelial cells and lung epithelial cells, as well as fibroblasts. 33,51 Ex vivo application of BIP (organ transplant and cell storage)…”

Genome instability in Alzheimer disease

“…These mice also have dementia (Borgesius et al, 2011). Ku deficient mice, which are compromised for DSB repair, displayed abnormal heart histology and function (Ngo et al, 2015) Since DNA damage can trigger vascular disease, a new prospect for prevention and treatment may be to focus on DNA damage prevention or increasing DNA repair capacity. DNA repair is important in vascular disease (Gray et al, 2015), and augmentation of DNA repair may have therapeutic benefits.…”