Low density lipoproteins promote unstable calcium handling accompanied by reduced SERCA2 and connexin-40 expression in cardiomyocytes.
Low density lipoproteins promote unstable calcium handling accompanied by reduced SERCA2 and connexin-40 expression in cardiomyocytes.
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DOI：
10.1371/journal.pone.0058128
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hove-Madsen L
中科院分区：
文献类型：
--
作者：
Barriga M;Cal R;Cabello N;Llach A;Vallmitjana A;Benítez R;Badimon L;Cinca J;Llorente-Cortés V;Hove-Madsen L
高血浆胆固醇水平对心血管系统的损害作用已广为人知，但对心肌细胞功能的直接影响却很少受到关注。因此，我们旨在验证低密度脂蛋白（LDL）胆固醇影响培养心房肌细胞钙动力学和信号传播的假设。为此，分别通过实时PCR和western blot分析测定mRNA和蛋白的表达水平，并在电场刺激下，在负载fluo-4的心房HL-1肌细胞培养中观察细胞内钙。在低刺激频率下，所有培养物在所有测试LDL浓度下均具有均匀的钙瞬变。500µg LDL/mL最大限度地使钙瞬态振幅从0.30±0.04降低到0.17±0.02，降幅达43% （p<0.05）。此外，当刺激间隔缩短时，ldl -胆固醇剂量依赖性地增加了交替和不规则搏动反应的比例。这种效应与SERCA2， RyR2， IP3RI和IP3RII mRNA水平的同时降低有关。200µg LDL/mL时，SERCA2蛋白水平也降低了43% (p<0.05)， SR钙负荷降低了38±6% （p<0.001）。相比之下，hdl -胆固醇对SERCA表达和SR钙负荷无显著影响。低密度脂蛋白胆固醇也使钙信号传导速度从无LDL时的3.2+0.2 mm/s减慢到500µg LDL/mL时的1.7±0.1 mm/s （p<0.05）。这与Cx40表达的减少（mRNA减少44±3%，p<0.05， Cx40蛋白在200µg/ml LDL时减少79±2%，p<0.05）相吻合，而Cx-43的表达没有显著变化。总之，ldl -胆固醇通过降低SERCA2和Cx40的表达和减慢钙信号的传导速度，在快速起搏的培养心房肌细胞中破坏钙处理的稳定性。
The damaging effects of high plasma levels of cholesterol in the cardiovascular system are widely known, but little attention has been paid to direct effects on cardiomyocyte function. We therefore aimed at testing the hypothesis that Low Density Lipoprotein (LDL) cholesterol affects calcium dynamics and signal propagation in cultured atrial myocytes. For this purpose, mRNA and protein expression levels were determined by real time PCR and western blot analysis, respectively, and intracellular calcium was visualized in fluo-4 loaded atrial HL-1 myocyte cultures subjected to field stimulation. At low stimulation frequencies all cultures had uniform calcium transients at all tested LDL concentrations. However, 500 µg LDL/mL maximally reduced the calcium transient amplitude by 43% from 0.30±0.04 to 0.17±0.02 (p<0.05). Moreover, LDL-cholesterol dose-dependently increased the fraction of alternating and irregular beat-to-beat responses observed when the stimulation interval was shortened. This effect was linked to a concurrent reduction in SERCA2, RyR2, IP3RI and IP3RII mRNA levels. SERCA2 protein levels were also reduced by 43% at 200 µg LDL/mL (p<0.05) and SR calcium loading was reduced by 38±6% (p<0.001). By contrast, HDL-cholesterol had no significant effect on SERCA expression or SR calcium loading. LDL-cholesterol also slowed the conduction velocity of the calcium signal from 3.2+0.2 mm/s without LDL to 1.7±0.1 mm/s with 500 µg LDL/mL (p<0.05). This coincided with a reduction in Cx40 expression (by 44±3%; p<0.05 for mRNA and by 79±2%; p<0.05 for Cx40 protein at 200 µg/ml LDL) whereas the Cx-43 expression did not significantly change. In conclusion, LDL-cholesterol destabilizes calcium handling in cultured atrial myocytes subjected to rapid pacing by reducing SERCA2 and Cx40 expression and by slowing the conduction velocity of the calcium signal.
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DOI：
10.1152/ajpheart.00816.2010
发表时间：
2011-03-01
影响因子：
4.8
作者：
Osadchii, Oleg E.;Soltysinska, Ewa;Olesen, Soren Peter
通讯作者：
Olesen, Soren Peter
影响因子：
5
作者：
Castellano, Jose;Farre, Jordi;Llorente-Cortes, Vicenta
通讯作者：
Llorente-Cortes, Vicenta
影响因子：
4.8
作者：
Muelhaeuser, Ulrike;Zolk, Oliver;Eschenhagen, Thomas
通讯作者：
Eschenhagen, Thomas
DOI：
10.1161/01.atv.0000193618.32611.8b
发表时间：
2006-01-01
影响因子：
8.7
作者：
Llorente-Cortés, V;Otero-Viñas, M;Badimon, L
通讯作者：
Badimon, L
影响因子：
7.3
作者：
Seto, S. W.;Au, A. L. S.;Kwan, Y. W.
通讯作者：
Kwan, Y. W.