Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.
Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.
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DOI：
10.1038/srep05847
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发表时间：
2014-08-01
影响因子：
4.6
通讯作者：
Nabeshima Y
中科院分区：
文献类型：
--
作者：
Nabeshima Y;Washida M;Tamura M;Maeno A;Ohnishi M;Shiroishi T;Imura A;Razzaque MS;Nabeshima Y
照顾好老年人是我们社会的一项重大挑战，因此需要确定潜在的药物靶点以减少与年龄相关的疾病负担。α-klotho-/-（α-kl）是一种寿命短的小鼠模型，显示出与人类衰老相关综合征相似的多种表型。α-kl-/-小鼠的这种衰老表型与蛋白水解酶Calpain-1的激活有关。我们假设钙蛋白酶-1的不受控制的激活可能导致α-kl缺陷小鼠的年龄相关表型。我们发现，每天服用BDA-410（一种钙蛋白酶-1抑制剂）显著改善了多种衰老相关表型。经治疗的小鼠表现出生殖能力恢复、体重增加、器官萎缩减少、异位钙化抑制、骨矿物质密度降低、肺气肿和老年性皮肤萎缩。我们还观察到α-kl-/-小鼠钙化动脉中FGF 23的异位表达，这可能解释了临床观察到的FGF 23水平升高与心血管死亡风险增加的相关性。这些发现使我们能够提出，钙蛋白酶-1活性的调节是一种潜在的治疗选择，用于延迟年龄相关的器官病理学，特别是由矿物离子稳态失调引起的。
Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho-/- (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl-/- mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl-/- mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.
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影响因子：
2.7
作者：
Narvaez, CJ;Zinser, G;Welsh, J
通讯作者：
Welsh, J
影响因子：
19.6
作者：
Moe, SM;Reslerova, M;Chen, NX
通讯作者：
Chen, NX
DOI：
10.1006/bbrc.2000.4226
发表时间：
2001-02-02
影响因子：
3.1
作者：
Koh, N;Fujimori, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
4
作者：
Alonso, L;Fuchs, E
通讯作者：
Fuchs, E
影响因子：
4.8
作者：
Dardenne, O;Prud'homme, J;St-Arnaud, R
通讯作者：
St-Arnaud, R