Inhibition of MicroRNA-146a and Overexpression of Its Target Dihydrolipoyl Succinyltransferase Protect Against Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction
Inhibition of MicroRNA-146a and Overexpression of Its Target Dihydrolipoyl Succinyltransferase Protect Against Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction
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DOI：
10.1161/circulationaha.116.024171
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发表时间：
2017-08-22
期刊：
影响因子：
37.8
通讯作者：
Heymans, Stephane
中科院分区：
文献类型：
--
作者：
Heggermont, Ward A.;Papageorgiou, Anna-Pia;Heymans, Stephane
背景：心血管疾病仍然是全球死亡的主要原因，心力衰竭的患病率持续增加。尽管增加了知识的代谢改变，发生在心力衰竭，新的治疗方法来治疗所观察到的代谢disorders.METHODS：小鼠进行压力超负荷的血管紧张素-II输注或横向主动脉缩窄。microRNA-146 a在心肌细胞中被基因敲除或基因敲除或基因过表达。此外，过表达的二氢硫辛酰琥珀酰转移酶（DLST）在小鼠心脏进行通过腺相关病毒。结果：microRNA-146 a在多个小鼠压力超负荷模型的整个心脏组织上调。此外，主动脉瓣狭窄患者的左心室活检中microRNA-146 a水平适度增加。心肌细胞中microRNA-146 a的过表达在体内引起心脏肥大和左心室功能障碍，而microRNA-146 a的基因敲除或药物阻断在体内减弱肥大反应并减轻心功能障碍。从机制上讲，microRNA-146 a减少了其靶DLST-α-酮戊二酸脱氢酶复合物的E2亚组分，这是一种控制三羧酸循环的酶。在野生型小鼠中，DLST蛋白水平在压力超负荷时显著降低，与氧化代谢降低平行，而DLST蛋白水平和因此氧化代谢在microRNA-146 a敲除小鼠中部分维持。此外，DLST在野生型小鼠中的过度表达保护心脏肥大和功能障碍invivo.CONCLUSIONS：总之，我们表明，microRNA-146 a和它的目标DLST是重要的代谢球员在左心室功能障碍。
BACKGROUND: Cardiovascular diseases remain the predominant cause of death worldwide, with the prevalence of heart failure continuing to increase. Despite increased knowledge of the metabolic alterations that occur in heart failure, novel therapies to treat the observed metabolic disturbances are still lacking.METHODS: Mice were subjected to pressure overload by means of angiotensin-II infusion or transversal aortic constriction. MicroRNA-146a was either genetically or pharmacologically knocked out or genetically overexpressed in cardiomyocytes. Furthermore, overexpression of dihydrolipoyl succinyltransferase (DLST) in the murine heart was performed by means of an adeno-associated virus.RESULTS: MicroRNA-146a was upregulated in whole heart tissue in multiple murine pressure overload models. Also, microRNA-146a levels were moderately increased in left ventricular biopsies of patients with aortic stenosis. Overexpression of microRNA-146a in cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of microRNA-146a blunted the hypertrophic response and attenuated cardiac dysfunction in vivo. Mechanistically, microRNA-146a reduced its target DLST-the E2 subcomponent of the a-ketoglutarate dehydrogenase complex, a rate-controlling tricarboxylic acid cycle enzyme. DLST protein levels significantly decreased on pressure overload in wild-type mice, paralleling a decreased oxidative metabolism, whereas DLST protein levels and hence oxidative metabolism were partially maintained in microRNA-146a knockout mice. Moreover, overexpression of DLST in wild-type mice protected against cardiac hypertrophy and dysfunction in vivo.CONCLUSIONS: Altogether we show that the microRNA-146a and its target DLST are important metabolic players in left ventricular dysfunction.