S-nitrosylation of transglutaminase 2 impairs fatty acid-stimulated contraction in hypertensive cardiomyocytes.
S-nitrosylation of transglutaminase 2 impairs fatty acid-stimulated contraction in hypertensive cardiomyocytes.
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转谷氨酰胺酶 2 的 S-亚硝基化损害高血压心肌细胞脂肪酸刺激的收缩
DOI：
10.1038/s12276-017-0021-x
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发表时间：
2018-04-06
影响因子：
12.8
通讯作者：
Zhang YH
中科院分区：
文献类型：
--
作者：
Jeong EM;Jin CZ;Jang JH;Zhao ZH;Jin CL;Lee JH;Lee KB;Kim SJ;Kim IG;Zhang YH
高血压心脏的心肌脂肪酸利用减少，收缩功能障碍，导致心力衰竭。然而，代谢重构和心肌细胞收缩力之间的因果关系仍然没有建立。已知转氨酶2（TG 2）通过调节线粒体功能促进ATP产生。在这项研究中，我们研究了TG 2参与脂肪酸补充下的心肌细胞收缩。使用TG 2抑制剂和TG 2缺陷小鼠，我们证明了脂肪酸补充激活TG 2并增加正常心脏心肌细胞的ATP水平和收缩力。相反，在血管紧张素II治疗的大鼠和小鼠的心肌细胞中，脂肪酸补充对TG 2活性、ATP水平和心肌细胞收缩的影响被消除。我们发现TG 2被S-亚硝基化抑制，并且在高血压心肌细胞中其水平增加。用神经元型NOS抑制剂治疗恢复脂肪酸诱导的TG 2活性增加和肌细胞收缩。此外，在正常和高血压心肌细胞中补充脂肪酸可增加细胞内Ca 2+水平，表明TG 2的S-亚硝基化而不是细胞内Ca 2+水平的改变是导致收缩功能障碍的原因。这些结果表明，TG 2通过促进脂肪酸代谢在调节心肌细胞收缩性中起关键作用，并为预防高负荷心脏收缩功能障碍提供了新的靶点。
The myocardium in hypertensive heart exhibits decreased fatty acid utilization and contractile dysfunction, leading to cardiac failure. However, the causal relationship between metabolic remodeling and cardiomyocyte contractility remains unestablished. Transglutaminase 2 (TG2) has been known to promote ATP production through the regulation of mitochondrial function. In this study, we investigated the involvement of TG2 in cardiomyocyte contraction under fatty acid supplementation. Using TG2 inhibitor and TG2-deficient mice, we demonstrated that fatty acid supplementation activated TG2 and increased ATP level and contractility of cardiac myocyte from the normal heart. By contrast, in cardiac myocytes from angiotensin-II-treated rats and mice, the effects of fatty acid supplementation on TG2 activity, ATP level, and myocyte contraction were abolished. We found that TG2 was inhibited byS-nitrosylation and its level increased in hypertensive myocytes. Treatment with inhibitor for neuronal NOS restored fatty acid-induced increase of TG2 activity and myocyte contraction. Moreover, intracellular Ca2+levels were increased by fatty acid supplementation in both normal and hypertensive myocytes, showing thatS-nitrosylation of TG2 but not alteration of intracellular Ca2+levels is responsible for contractile dysfunction. These results indicate that TG2 plays a critical role in the regulation of myocyte contractility by promoting fatty acid metabolism and provide a novel target for preventing contractile dysfunction in heart with high workload.
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影响因子：
4.5
作者：
Min SK;Min SI;Jeong EM;Cho SY;Ha J;Kim SJ;Kim IG
通讯作者：
Kim IG
影响因子：
3.5
作者：
Collighan, R. J.;Griffin, M.
通讯作者：
Griffin, M.
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5.3
作者：
De Laurenzi, V;Melino, G
通讯作者：
Melino, G
影响因子：
5.3
作者：
Yamaguchi, H;Wang, HG
通讯作者：
Wang, HG
影响因子：
4.4
作者：
Falasca, Laura;Farrace, Maria Grazia;Piacentini, Mauro
通讯作者：
Piacentini, Mauro