Hypoxia exacerbates Ca2+-handling disturbances induced by very low density lipoproteins (VLDL) in neonatal rat cardiomyocytes
Hypoxia exacerbates Ca2+-handling disturbances induced by very low density lipoproteins (VLDL) in neonatal rat cardiomyocytes
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DOI：
10.1016/j.yjmcc.2011.02.002
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发表时间：
2011-05-01
影响因子：
5
通讯作者：
Llorente-Cortes, Vicenta
中科院分区：
文献类型：
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作者：
Castellano, Jose;Farre, Jordi;Llorente-Cortes, Vicenta
众所周知，心肌在缺血条件下会发生严重的改变，如脂质过载和电生理学改变。然而，目前尚不清楚在缺血条件下细胞内脂质积聚和钙功能障碍是否具有共同的病理生理机制。本研究的目的是：1）分析正常和高剂量极低密度脂蛋白（VLDL）对脂质含量和钙处理的影响; 2）研究缺氧是否调节高VLDL剂量的影响; 3）确定心肌细胞中潜在的潜在机制。为此，从3-4日龄大鼠的心脏制备新生大鼠心室肌细胞培养物。高剂量的VLDL诱导胆固醇酯（CE）和甘油三酯（TG）的积累强烈降低肌浆网（内）钙ATP酶-2（SERCA-2）的表达，钙瞬时振幅和肌浆网（SR）的钙负荷。有趣的是，缺氧通过上调VLDL受体表达（16 h时为4.5倍）增加CE（1.5倍）和TG（3倍）心肌细胞含量，并加剧VLDL对SERCA-2表达的负面影响。在功能上，VLDL介导的SERCA-2下调的缺氧加重被转化为同时暴露于缺氧和高VLDL的心肌细胞中的钙瞬变幅度和SR钙负荷的更强的降低。总之，高VLDL剂量改变心肌细胞中的钙处理，并且SERCA-2在VLDL介导的对心脏钙处理的作用的缺氧加重中起关键作用。低氧条件下VLDL作用的增强至少部分是通过低氧上调VLDL受体的表达来解释的。(C)2011爱思唯尔有限公司保留所有权利。
It is known that myocardium suffers serious alterations under ischemic conditions such as lipid overloading and electrophysiological alterations. However, it is unknown whether intracellular lipid accumulation and calcium dysfunction share common pathophysiological mechanisms under ischemia. The aims of this study were 1) to analyze the effect of normal and high doses of very low density lipoproteins (VLDL) on lipid content and calcium handling; 2) to investigate whether hypoxia modulates the effect of high VLDL doses; and 3) to identify potentially underlying mechanisms in cardiomyocytes. For this purpose, neonatal rat ventricular myocytes cultures were prepared from hearts of 3-4-day-old rats. High doses of VLDL that induced cholesteryl ester (CE) and triglyceride (TG) accumulation strongly reduced sarco(endo)plasmic reticulum Ca ATPase-2 (SERCA-2) expression, calcium transient amplitude and sarcoplasmic reticulum (SR) calcium loading. Interestingly, hypoxia, by upregulating VLDL-receptor expression (4.5-fold at 16 h) increased CE (1.5-fold) and TG (3-fold) cardiomyocyte content and exacerbated the negative effect of VLDL on SERCA-2 expression. Functionally, the hypoxic exacerbation of VLDL-mediated SERCA-2 downregulation was translated into a stronger decrease in calcium transient amplitude and SR calcium loading in myocytes exposed simultaneously to hypoxia and high VLDL In conclusion, high VLDL doses alter calcium handling in cardiomyocytes and SERCA-2 play a pivotal role in the hypoxic exacerbation of VLDL-mediated effects on cardiac calcium handling. Potentiation of VLDL's effects under hypoxia is explained, at least in part, by hypoxic upregulation of the expression of VLDL-receptor. (C) 2011 Elsevier Ltd. All rights reserved.