Li Lan-Lan, Sun Chao-Jun, Mo Xiao-Tong, Xing Yun, Zhang Tong, Zhang Heng, Zhao Nan, Zeng Xiao-Feng, Wang Sha-Sha, Meng Yan-Yan, Xie Sai-Yang, Deng Wei
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China.
Acta Pharmacol Sin. 2025 Sep 12. doi: 10.1038/s41401-025-01637-0.
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.
病理性心脏肥大是心力衰竭的主要原因，其机制复杂。富马酸水合酶（FH）是三羧酸循环中的关键酶。FH突变和功能障碍与多种病理过程有关，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。在本研究中，我们调查了FH在心脏肥大中的作用。通过横向主动脉缩窄（TAC）手术诱导小鼠心脏肥大，并通过苯肾上腺素（PE）刺激诱导新生大鼠心肌细胞（NRCMs）肥大。我们发现，在TAC小鼠中，FH的表达水平随着心脏肥大的发展而逐渐升高。在TAC手术前两周通过静脉注射携带FH的重组腺相关病毒血清型9（AAV9）进行心肌细胞特异性FH过表达，可预防TAC小鼠的形态学变化、心脏功能障碍和重塑；FH过表达还显著减轻了PE诱导的NRCMs肥大，同时抑制了肥大标志物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，并促进了代谢重塑。RNA测序和非靶向代谢组学显示，FH过表达主要通过抑制转录因子SREBP和降低超长链脂肪酸延伸蛋白7（Elovl7）的基因表达，减轻了TAC小鼠的心肌重塑和线粒体代谢功能障碍。Elovl7的过表达逆转了FH对TAC小鼠和PE刺激的NRCMs的保护作用。转录因子SREBP的敲低降低了Elovl7的表达，从而发挥了心脏保护作用。总之，我们证明FH过表达通过苹果酸-SREBP-Elovl7途径调节葡萄糖和脂质代谢，从而预防小鼠心脏肥大。
