nNOS介导的TG2-SNO信号通路在心力衰竭心脏能量代谢中的作用及分子机制研究

Heart failure, the final stage of most cardiovascular diseases, is the main cause of high mortality in patients. The energy metabolism of cardiomyocytes plays an important role in the initiation and progression of heart failure. Transglutaminase 2 (TG2) regulates mitochondrial ATP production and transport by regulating respiratory chain complexes and ADP/ATP transporters. NO-dependent S-nitrosylation of TG2 (TG2-SNO) can lead to TG2 inactivation. Previous studies have found that in the failed heart, Neuronal nitric oxide synthase (nNOS) is upregulated and inhibits TG2 activity, suggesting that the nNOS-mediated TG2-SNO signaling pathway plays an important role in the energy metabolism of a failed heart. However, intracellular localization and the related signal regulatory mechanism of this pathway have not yet been elucidated. Therefore, the applicant intends to establish an animal model of heart failure, by examining the changes of energy metabolism, to clarify the molecular mechanisms by which the upregulated nNOS inhibits the production and transport of mitochondrial ATP through the TG2-SNO signaling pathway. Thereby, the applicant hopes to provide a new theoretical basis for exploring and developing new anti-heart failure drugs.

心力衰竭作为大多数心血管疾病发生发展的终末阶段，是心血管疾病的高致死率的主要原因。其心肌细胞能量代谢在心力衰竭发生发展中发挥重要作用。谷氨酰胺转氨酶2（TG2）通过调节呼吸链复合体和ADP/ATP转运体来调节线粒体ATP的生成与转运。NO依赖的TG2巯基亚硝基化（TG2-SNO）导致TG2的失活。前期研究中发现，在心力衰竭心脏中神经型一氧化氮合酶（nNOS）上调并抑制TG2活性。提示nNOS介导的TG2-SNO信号通路在心力衰竭心脏能量代谢中发挥重要作用。 但迄今，细胞内定位及相关信号调节机制尚不明确。因此，申请人拟建立心力衰竭动物模型，通过能量代谢的变化及其分子机制的研究，阐明心力衰竭心脏中上调的nNOS通过TG2-SNO信号通路抑制线粒体ATP生成和转运的分子机制，从而为探索及研发新的抗心力衰竭药物提供新的理论依据。

心脏能量代谢在心力衰竭发生发展中发挥重要作用。心力衰竭时上调的nNOS通过增加TG2巯基亚硝基化(TG2-SNO)，抑制心肌能量代谢，其分子机制为通过心力衰竭模型左心室心肌细胞中，神经型一氧化氮合酶(nNOS)蛋白质表达增多；nNOS依赖的TG2-SNO显著增加，TG2活性减弱；脂肪酸氧化生成的ATP含量减少，心脏所需能量不足，降低心肌细胞收缩功能。本研究通过建立高血压诱导的心力衰竭模型，探讨心力衰竭心脏中，心脏能量代谢的变化及其分子机制；揭示了nNOS通过TG2活性来调节线粒ATP生成的分子机制，阐明心力衰竭时，心脏主要能量来源即脂肪酸β氧化被抑制的分子机制，从而寻找新的、有临床意义的治疗靶点，并为今后的科学研究提供研究线索及理论基础。项目资助发表期刊论文4篇，荣获延边朝鲜族自治州科技进步奖，培养硕士研究生4名。