SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure.
SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure.
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DOI：
10.1155/2015/251598
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发表时间：
2015
影响因子：
--
通讯作者：
Shull GE
中科院分区：
文献类型：
--
作者：
Prasad V;Lorenz JN;Lasko VM;Nieman ML;Huang W;Wang Y;Wieczorek DW;Shull GE
编码肌浆网/内质网Ca 2 +-ATP酶亚型2（SERCA 2）的基因ATP 2A 2的一个拷贝中的突变导致人类Darier病，这是一种涉及角质形成细胞的皮肤病。在Darier病患者中，心脏功能似乎未受损，没有证据表明SERCA 2单倍不足本身会导致心脏病。然而，SERCA 2缺乏被广泛认为是心力衰竭的一个促成因素。因此，我们分析了Atp 2a 2杂合子小鼠，以确定SERCA 2单倍不足是否会加重特定的心脏疾病。尽管心脏中SERCA 2a水平降低，Atp 2a 2杂合小鼠在表现出正常心脏生理学方面与人类相似。当受到甲状腺功能减退症或交叉的转基因模型降低肌原纤维钙敏感性，SERCA 2缺乏引起的疾病状态没有增强。然而，当与肌原纤维Ca 2+敏感性增加的转基因模型结合时，SERCA 2单倍不足引起肥大、失代偿和死亡的快速发作。这些影响与抗凋亡Hax 1的表达减少，促凋亡基因Chop和Casp 12的水平增加，以及能量代谢紊乱的证据有关。这些数据揭示肌原纤维Ca 2+敏感性是SERCA 2单倍不足的心脏效应的重要决定因素，并提高了Darier病患者在某些条件下更容易发生心力衰竭的可能性。
Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), cause Darier disease in humans, a skin condition involving keratinocytes. Cardiac function appears to be unimpaired in Darier disease patients, with no evidence that SERCA2 haploinsufficiency itself causes heart disease. However, SERCA2 deficiency is widely considered a contributing factor in heart failure. We therefore analyzed Atp2a2 heterozygous mice to determine whether SERCA2 haploinsufficiency can exacerbate specific heart disease conditions. Despite reduced SERCA2a levels in heart, Atp2a2 heterozygous mice resembled humans in exhibiting normal cardiac physiology. When subjected to hypothyroidism or crossed with a transgenic model of reduced myofibrillar Ca2+-sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca2+-sensitivity, SERCA2 haploinsufficiency caused rapid onset of hypertrophy, decompensation, and death. These effects were associated with reduced expression of the antiapoptotic Hax1, increased levels of the proapoptotic genes Chop and Casp12, and evidence of perturbations in energy metabolism. These data reveal myofibrillar Ca2+-sensitivity to be an important determinant of the cardiac effects of SERCA2 haploinsufficiency and raise the possibility that Darier disease patients are more susceptible to heart failure under certain conditions.
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DOI：
10.1111/dom.12248
发表时间：
2014-08
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Haynie KR;Vandanmagsar B;Wicks SE;Zhang J;Mynatt RL
通讯作者：
Mynatt RL
DOI：
10.1152/ajpheart.00075.2014
发表时间：
2014-04-01
影响因子：
4.8
作者：
Collins, Helen E.;He, Lan;Chatham, John C.
通讯作者：
Chatham, John C.
影响因子：
3.7
作者：
Curcio A;Torella D;Iaconetti C;Pasceri E;Sabatino J;Sorrentino S;Giampà S;Micieli M;Polimeni A;Henning BJ;Leone A;Catalucci D;Ellison GM;Condorelli G;Indolfi C
通讯作者：
Indolfi C
影响因子：
20.1
作者：
HOLUBARSCH, C;GOULETTE, RP;ALPERT, NR
通讯作者：
ALPERT, NR
影响因子：
2.4
作者：
Kataoka, Aya;Hemmer, Carolyn;Chase, P. Bryant
通讯作者：
Chase, P. Bryant