Calcitriol modulation of cardiac contractile performance via protein kinase C
Calcitriol modulation of cardiac contractile performance via protein kinase C
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DOI：
10.1016/j.yjmcc.2006.05.019
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发表时间：
2006-08-01
影响因子：
5
通讯作者：
Westfall, Margaret V.
中科院分区：
文献类型：
--
作者：
Green, John J.;Robinson, Dustin A.;Westfall, Margaret V.
实验研究表明，维生素 D-3 缺乏会增强心脏收缩，但矛盾的是，这种缺乏与人类充血性心力衰竭有关。活化的维生素 D-3（1 α,25-二羟基维生素 D-3）或骨化三醇可降低离体灌注心脏中的峰值力并激活蛋白激酶 C (PKC)。然而，这种激素对成人心肌细胞收缩功能的直接影响尚不清楚。我们的目的是研究 1,25-二羟基维生素 D-3 是否通过 PKC 激活成年大鼠心肌细胞急性调节收缩功能。在从成年大鼠心脏分离的电刺激肌细胞中测量肌节缩短和再延长，并将维生素D-3反应（10(-10)至10(-7)M）与基础条件下观察到的缩短进行比较。使用10(-9) M 1 α,25-二羟基维生素D-3观察到肌节缩短和松弛的最大变化。该剂量减少了峰值缩短，并在给药后 5 分钟内加速了收缩和舒张速率，Ca2+瞬态的变化导致了峰值缩短和舒张效应。 PKC抑制剂双吲哚马来酰亚胺(500 nM)很大程度上阻断了最有效剂量(10(-9) M)对收缩功能的急性影响。虽然峰值缩短和缩短率在 30 分钟内恢复到基线，但松弛持续加速，持续超过 60 分钟。 Ca2+ 调节蛋白、受磷蛋白和心肌肌钙蛋白 I 的磷酸化与急性应用 1 α,25-二羟基维生素 D-3 时观察到的加速松弛相关。长期添加 1α,25-二羟基维生素 D-3（例如 2 天）后，继续观察到加速松弛，但这种松弛的持续增加与受磷蛋白或肌钙蛋白 1 的磷酸化增加无关。这些结果提供了证据，表明 1α,25-二羟基维生素 D-3 直接调节成体肌细胞收缩功能，而蛋白激酶 C 在急性反应中发挥重要的信号作用。该激酶对关键 Ca2+ 调节蛋白的磷酸化有助于增强对急性而非慢性骨化三醇反应所观察到的松弛。 (c) 2006 Elsevier Inc. 保留所有权利。
Vitamin D-3 deficiency enhances cardiac contraction in experimental studies, yet paradoxically this deficiency is linked to congestive heart failure in humans. Activated vitamin D-3 (1 alpha,25-dihydroxyvitamin D-3) or calcitriol, decreases peak force and activates protein kinase C (PKC) in isolated perfused hearts. However, the direct influence of this hormone on adult cardiac myocyte contractile function is not well understood. Our aim is to investigate whether 1,25-dihydroxyvitamin D-3 acutely modulates contractile function via PKC activation in adult rat cardiac myocytes. Sarcomere shortening and re-lengthening were measured in electrically stimulated myocytes isolated from adult rat hearts, and the vitamin D-3 response (10(-10) to 10(-7) M) was compared to shortening observed under basal conditions. Maximum changes in sarcomere shortening and relaxation were observed with 10(-9) M 1 alpha,25-dihydroxyvitamin D-3. This dose decreased peak shortening, and accelerated contraction and relaxation rates within 5 min of administration, and changes in the Ca2+ transient contributed to the peak shortening and relaxation effects. The PKC inhibitor, bis-indolylmaleimide (500 nM) largely blocked the acute influence of the most potent dose (10(-9) M) on contractile function. While peak shortening and shortening rate returned to baseline within 30 min, there was a sustained acceleration of relaxation that continued over 60 min. Phosphorylation of the Ca2+ regulatory proteins, phospholamban, and cardiac troponin I correlated with the accelerated relaxation observed in response to acute application of 1 alpha,25-dihydroxyvitamin D-3. Accelerated relaxation continued to be observed after chronic addition of 1 alpha,25-dihydroxyvitamin D-3 (e.g. 2 days), yet this sustained increase in relaxation was not associated with increased phosphorylation of phospholamban or troponin 1. These results provide evidence that 1 alpha,25-dihydroxyvitamin D-3 directly modulates adult myocyte contractile function, and protein kinase C plays an important signaling role in the acute response. Phosphorylation of key Ca2+ regulatory proteins by this kinase contributes to the enhanced relaxation observed in response to acute, but not chronic calcitriol. (c) 2006 Elsevier Inc. All rights reserved.