Abnormal calcium handling and exaggerated cardiac dysfunction in mice with defective vitamin d signaling.
Abnormal calcium handling and exaggerated cardiac dysfunction in mice with defective vitamin d signaling.
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DOI：
10.1371/journal.pone.0108382
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kang PM
中科院分区：
文献类型：
--
作者：
Choudhury S;Bae S;Ke Q;Lee JY;Singh SS;St-Arnaud R;Monte FD;Kang PM
改变的维生素D信号与心功能不全有关，但致病机制尚不清楚。我们研究了维生素D信号在心功能障碍发展中的作用和机制。我们分析了1α-羟化酶（1α-OHase）敲除（1α-OHase−/−）小鼠，这些小鼠缺乏将非活性形式的维生素D转化为体内活性形式的1α-OH酶。1α-OHase−/−小鼠在基线时显示中度心脏肥大。通过横向主动脉缩窄（TAC）诱导的压力超负荷显示，与WT同窝小鼠相比，1α-OHase−/−小鼠的心功能障碍加重，纤维化和炎性细胞因子表达显著增加。钙（Ca 2+）瞬变分析表明1α-OHase−/−小鼠心肌细胞（CM）中存在严重的Ca 2+处理异常，帕立骨化醇（PC）（一种活化维生素D3类似物）处理可显著减弱1α-OHase−/− CM中Ca 2+处理缺陷。我们通过首先纠正1α-OHase−/−小鼠的维生素D缺乏症，然后在假手术或TAC时每日维持剂量的维生素D或溶剂（以达到维生素D缺乏症），进一步描述了维生素D缺乏症对TAC的影响。与溶剂处理的动物相比，在维生素D处理的小鼠中，TAC诱导的心脏肥大、间质纤维化、炎症标志物、Ca 2+处理异常和心脏功能显著减弱。我们的研究结果提供了对心功能不全机制的深入了解，这与1α-OHase−/−小鼠中严重缺陷的Ca 2+处理和缺陷的维生素D信号传导有关。
Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction. We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase−/−) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase−/− mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase−/− mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase−/− CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase−/− mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals. Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase−/− mice.
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影响因子：
37.8
作者：
Kubo, H;Margulies, KB;Houser, SR
通讯作者：
Houser, SR
影响因子：
6.2
作者：
Dardenne, O;Prud'Homme, J;St-Arnaud, R
通讯作者：
St-Arnaud, R
DOI：
10.1073/pnas.0611202104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Bodyak, Natalya;Ayus, Juan Carlos;Kang, Peter M.
通讯作者：
Kang, Peter M.
影响因子：
4.8
作者：
Dardenne, O;Prud'homme, J;St-Arnaud, R
通讯作者：
St-Arnaud, R
影响因子：
15.9
作者：
PERREAULT, CL;SHANNON, RP;MORGAN, JP
通讯作者：
MORGAN, JP