Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.

IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Lan-Lan Li, Chao-Jun Sun, Xiao-Tong Mo, Yun Xing, Tong Zhang, Heng Zhang, Nan Zhao, Xiao-Feng Zeng, Sha-Sha Wang, Yan-Yan Meng, Sai-Yang Xie, Wei Deng
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引用次数: 0

Abstract

Pathological cardiac hypertrophy as a major contributor to heart failure is characterized by complicated mechanisms. Fumarate hydratase (FH) is a crucial enzyme in the tricarboxylic acid cycle. FH mutations and dysfunction have been implicated in various pathological processes including hereditary leiomyomatosis and renal cell cancer, neurodegenerative diseases, metabolic syndrome and cardiovascular diseases. In this study we investigated the role of FH in cardiac hypertrophy. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery as well as in neonatal rat cardiomyocytes (NRCMs) by phenylephrine (PE) stimulation. We showed that the expression levels of FH were gradually increased with development of cardiac hypertrophy in TAC mice. Cardiomyocyte-specific overexpression of FH by intravenous injection of recombinant adeno-associated virus serotype 9 (AAV9) carrying FH two weeks before TAC surgery prevented the morphological changes, cardiac dysfunction and remodeling in TAC mice; FH overexpression also significantly attenuated PE-induced hypertrophy in NRCMs along with suppressed expression of hypertrophic markers ANP, BNP and β-MHC. We demonstrated that FH overexpression alleviated TAC-induced mitochondrial structural damage in cardiomyocytes and facilitated metabolic remodeling. RNA sequencing and untargeted metabolomics revealed that FH overexpression mitigated myocardial remodeling and mitochondrial metabolism dysfunction in TAC mice mainly by suppressing the transcription factor SREBP and reducing the gene expression of elongation of very long chain fatty acids protein 7 (Elovl7). Overexpression of Elovl7 reversed the protective effects of FH in both TAC mice and PE-stimulated NRCMs. Knockdown of the transcription factor SREBP reduced Elovl7 expression, thereby exerting cardioprotective effects. In conclusion, we demonstrate that FH overexpression prevents cardiac hypertrophy in mice by regulating glucose and lipid metabolism through the malate-SREBP-Elovl7 pathway.

富马酸水合酶通过控制elovl7介导的不饱和脂肪酸的生物合成来改善压力过载引起的心脏重构。
病理性心肌肥厚是导致心力衰竭的主要因素,其机制复杂。富马酸水合酶(FH)是三羧酸循环中的重要酶。FH突变和功能障碍涉及多种病理过程,包括遗传性平滑肌瘤病和肾细胞癌、神经退行性疾病、代谢综合征和心血管疾病。本研究探讨FH在心肌肥厚中的作用。横断主动脉缩窄术(TAC)诱导小鼠心肌肥厚,苯肾上腺素(PE)刺激新生大鼠心肌细胞(NRCMs)。我们发现,随着TAC小鼠心肌肥厚的发展,FH的表达水平逐渐升高。TAC术前2周静脉注射携带FH的重组腺相关病毒血清型9 (AAV9),心肌细胞特异性过表达FH,可防止TAC小鼠形态学改变、心功能障碍和重构;FH过表达还能显著减轻pe诱导的nrcm肥厚,同时抑制肥厚标志物ANP、BNP和β-MHC的表达。我们证明,FH过表达减轻了tac诱导的心肌细胞线粒体结构损伤,促进了代谢重塑。RNA测序和非靶向代谢组学研究显示,FH过表达主要通过抑制转录因子SREBP和降低超长链脂肪酸蛋白7 (Elovl7)的表达来减轻TAC小鼠心肌重构和线粒体代谢功能障碍。在TAC小鼠和pe刺激的nrcm中,Elovl7的过表达逆转了FH的保护作用。敲低转录因子SREBP可降低Elovl7的表达,从而发挥心脏保护作用。总之,我们证明FH过表达通过苹果酸- srebp - elovl7通路调节糖脂代谢,从而防止小鼠心脏肥厚。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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