Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling.
Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling.
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DOI：
10.1126/scisignal.2005046
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发表时间：
2014-03-18
影响因子：
7.3
通讯作者：
Chen-Izu Y
中科院分区：
文献类型：
--
作者：
Jian Z;Han H;Zhang T;Puglisi J;Izu LT;Shaw JA;Onofiok E;Erickson JR;Chen YJ;Horvath B;Shimkunas R;Xiao W;Li Y;Pan T;Chan J;Banyasz T;Tardiff JC;Chiamvimonvat N;Bers DM;Lam KS;Chen-Izu Y
在每一次心跳中，心肌细胞都会因机械负荷而收缩，过度的机械压力会导致心脏病。利用凝胶中细胞系统在心肌细胞收缩过程中施加后负荷，我们发现一氧化氮合酶(NOS)参与了机械负荷的传递以改变钙动力学。在小鼠心室肌细胞中，后负荷增加了收缩时的钙瞬变，从而增强了对抗机械负荷的收缩能力，但也引起了舒张期自发的钙火花，这可能是致心律失常的。钙瞬变和火花的增加归因于Ryanodine受体(RyR)敏感性的增加，因为肌浆网负荷中的钙含量没有变化。药物抑制或nNOS(或NOS1)的基因缺失，但不能阻止eNOS(或NOS3)的基因缺失，均可阻止后负荷引起的钙火花。这种不同的效应可能是由超分辨率成像确定的nNOS接近RyR引起的局部NO信号引起的。钙调素依赖的蛋白激酶II(CaMKII)和烟酰胺腺嘌呤二核苷酸磷酸氧化酶2(NOX2)也参与了后负荷诱发的钙火花。家族性肥厚型心肌病小鼠模型的心肌细胞表现出增强的机械转导和频繁的致心律失常的钙离子火花。抑制心肌细胞中的nNOS和CaMKII，但不抑制NOX2，可消除钙离子火花，提示机械转导独立于NOX2激活nNOS和CaMKII。因此，我们的数据确定nNOS、CaMKII和NOX2是心脏收缩过程中机械性化学转导的关键介质，这为治疗机械应激诱导的钙调节失调、心律失常和心肌病提供了新的治疗靶点。
Cardiomyocytes contract against a mechanical load during each heartbeat, and excessive mechanical stress leads to heart diseases. Using a cell-in-gel system that imposes an afterload during cardiomyocyte contraction, we found that nitric oxide synthase (NOS) was involved in transducing mechanical load to alter Ca2+ dynamics. In mouse ventricular myocytes, afterload increased the systolic Ca2+ transient, which enhanced contractility to counter mechanical load, but also caused spontaneous Ca2+ sparks during diastole that could be arrhythmogenic. The increases in the Ca2+ transient and sparks were attributable to increased ryanodine receptor (RyR) sensitivity because the amount of Ca2+ in the sarcoplasmic reticulum load was unchanged. Either pharmacological inhibition or genetic deletion of nNOS (or NOS1), but not of eNOS (or NOS3), prevented afterload-induced Ca2+ sparks. This differential effect may arise from localized NO signaling, arising from the proximity of nNOS to RyR, as determined by super-resolution imaging. Ca2+-calmodulin–dependent protein kinase II (CaMKII) and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) also contributed to afterload-induced Ca2+ sparks. Cardiomyocytes from a mouse model of familial hypertrophic cardiomyopathy exhibited enhanced mechanotransduction and frequent arrhythmogenic Ca2+ sparks. Inhibiting nNOS and CaMKII, but not NOX2, in cardiomyocytes from this model eliminated the Ca2+ sparks, suggesting mechanotransduction activated nNOS and CaMKII independently from NOX2. Thus, our data identify nNOS, CaMKII, and NOX2 as key mediators in mechanochemotransduction during cardiac contraction, which provides new therapeutic targets for treating mechanical stress–induced Ca2+ dysregulation, arrhythmias, and cardiomyopathy.
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影响因子：
20.1
作者：
Alvarez, BV;Pérez, NG;Cingolani, HE
通讯作者：
Cingolani, HE
影响因子：
37.8
作者：
MARON, BJ;GARDIN, JM;BILD, DE
通讯作者：
BILD, DE
影响因子：
3.4
作者：
Cheng, H;Song, LS;Stern, MD
通讯作者：
Stern, MD
影响因子：
64.5
作者：
Erickson, Jeffrey R.;Joiner, Mei-ling A.;Anderson, Mark E.
通讯作者：
Anderson, Mark E.
影响因子：
3.4
作者：
Chen-Izu, Ye;McCulle, Stacey L.;Izu, Leighton T.
通讯作者：
Izu, Leighton T.