Glucose-6-phosphate dehydrogenase and NADPH redox regulates cardiac myocyte L-type calcium channel activity and myocardial contractile function.
Glucose-6-phosphate dehydrogenase and NADPH redox regulates cardiac myocyte L-type calcium channel activity and myocardial contractile function.
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DOI：
10.1371/journal.pone.0045365
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gupte SA
中科院分区：
文献类型：
--
作者：
Rawat DK;Hecker P;Watanabe M;Chettimada S;Levy RJ;Okada T;Edwards JG;Gupte SA
我们最近证明，17-酮类固醇，表雄酮，减弱心肌细胞的L型钙电流（ICa-L），抑制心肌收缩力。由于已知17-酮类类固醇抑制葡萄糖-6-磷酸脱氢酶（G6 PD）（戊糖磷酸途径中的限速酶），并降低细胞内NADPH水平，因此我们假设G6 PD的抑制可能是一种新的抑制ICa-L的信号传导机制，从而抑制心脏收缩功能。我们通过检测离体心脏的心肌功能和离体心肌细胞的钙通道活性来验证这一观点。在Langendorff灌注的心脏中测试心肌功能，并通过从−80 mV的保持电位施加双脉冲，然后标准化为对照电流的峰值幅度，在全细胞贴片配置中记录ICa-L。6-氨基烟酰胺是G6 PD的竞争性抑制剂，可增加pCO 2和降低pH。此外，6-氨基烟酰胺可抑制G6 PD活性，降低NADPH水平，减弱峰值ICa-L幅度，并降低左心室发展压力和±dp/dt。最后，将NADPH从贴片移液管溶液透析到细胞中减弱了6-氨基烟酰胺对ICa-L的抑制。同样，在G6 PD缺陷小鼠中，心脏中G6 PD不足降低了GSH与GSSG的比率、超氧化物、胆固醇和乙酰辅酶A。在这些小鼠中，M型超声心动图结果显示舒张期容积和舒张末期直径增加，而缩短分数无变化。总之，这些发现表明，抑制G6 PD活性和降低NADPH水平改变代谢，并导致抑制L型Ca 2+通道活性。值得注意的是，该途径可能涉及在生理和病理生理条件下调节心肌收缩性，在此期间，戊糖磷酸途径衍生的NADPH氧化还原被调节（例如，缺血-再灌注和心力衰竭）。
We recently demonstrated that a 17-ketosteroid, epiandrosterone, attenuates L-type Ca2+ currents (ICa-L) in cardiac myocytes and inhibits myocardial contractility. Because 17-ketosteroids are known to inhibit glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, and to reduce intracellular NADPH levels, we hypothesized that inhibition of G6PD could be a novel signaling mechanism which inhibit ICa-L and, therefore, cardiac contractile function. We tested this idea by examining myocardial function in isolated hearts and Ca2+ channel activity in isolated cardiac myocytes. Myocardial function was tested in Langendorff perfused hearts and ICa-L were recorded in the whole-cell patch configuration by applying double pulses from a holding potential of −80 mV and then normalized to the peak amplitudes of control currents. 6-Aminonicotinamide, a competitive inhibitor of G6PD, increased pCO2 and decreased pH. Additionally, 6-aminonicotinamide inhibited G6PD activity, reduced NADPH levels, attenuated peak ICa-L amplitudes, and decreased left ventricular developed pressure and ±dp/dt. Finally, dialyzing NADPH into cells from the patch pipette solution attenuated the suppression of ICa-L by 6-aminonicotinamide. Likewise, in G6PD-deficient mice, G6PD insufficiency in the heart decreased GSH-to-GSSG ratio, superoxide, cholesterol and acetyl CoA. In these mice, M-mode echocardiographic findings showed increased diastolic volume and end-diastolic diameter without changes in the fraction shortening. Taken together, these findings suggest that inhibiting G6PD activity and reducing NADPH levels alters metabolism and leads to inhibition of L-type Ca2+ channel activity. Notably, this pathway may be involved in modulating myocardial contractility under physiological and pathophysiological conditions during which the pentose phosphate pathway-derived NADPH redox is modulated (e.g., ischemia-reperfusion and heart failure).
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DOI：
10.1152/ajpheart.00229.2003
发表时间：
2003-12-01
影响因子：
4.8
作者：
Gupte, SA;Arshad, M;Wolin, MS
通讯作者：
Wolin, MS
影响因子：
6
作者：
Gupte, Rakhee S.;Vijay, Venkataramana;Gupte, Sachin A.
通讯作者：
Gupte, Sachin A.
DOI：
10.1152/ajpheart.00629.2004
发表时间：
2005-01-01
影响因子：
4.8
作者：
Gupte, SA;Kaminski, PM;Wolin, MS
通讯作者：
Wolin, MS
影响因子：
64.8
作者：
LEE, KS;TSIEN, RW
通讯作者：
TSIEN, RW
影响因子：
7.3
作者：
JIANG, C;POOLEWILSON, PA;MACLEOD, KT
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MACLEOD, KT