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用依托莫西通过抑制CPT1逆转代谢重编程可促进心肌细胞增殖和心脏再生 DUSP1 ADP-核糖基化介导的p38 MAPK磷酸化。

Reversing metabolic reprogramming by CPT1 inhibition with etomoxir promotes cardiomyocyte proliferation and heart regeneration DUSP1 ADP-ribosylation-mediated p38 MAPK phosphorylation.

作者信息

Tang Luxun, Shi Yu, Liao Qiao, Wang Feng, Wu Hao, Ren Hongmei, Wang Xuemei, Fu Wenbin, Shou Jialing, Wang Wei Eric, Jose Pedro A, Yang Yongjian, Zeng Chunyu

机构信息

Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400042, China.

Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing 400042, China.

出版信息

Acta Pharm Sin B. 2025 Jan;15(1):256-277. doi: 10.1016/j.apsb.2024.11.001. Epub 2024 Nov 7.

DOI:10.1016/j.apsb.2024.11.001
PMID:40041918
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11873623/
Abstract

The neonatal mammalian heart has a remarkable regenerative capacity, while the adult heart has difficulty to regenerate. A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth. In this study, we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation. Reversing metabolic reprogramming by carnitine palmitoyltransferase 1 (CPT1) inhibition, using cardiac-specific and knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction. The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir, a CPT1 inhibitor. CPT1 inhibition, by decreasing poly(ADP-ribose) polymerase 1 expression, reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes, leading to decreased p38 MAPK phosphorylation, and stimulation of cardiomyocyte proliferation. Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation. CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.

摘要

新生哺乳动物心脏具有显著的再生能力，而成体心脏再生困难。出生后不久，随着心肌细胞增殖能力的丧失，会发生从糖酵解到脂肪酸氧化的代谢重编程。在本研究中，我们试图确定代谢重编程是否以及如何调节心肌细胞增殖。通过抑制肉碱棕榈酰转移酶1（CPT1）来逆转代谢重编程，使用心脏特异性敲除小鼠，促进了心肌细胞增殖并改善了心肌梗死后的心脏功能。CPT1抑制具有药理学意义，因为这些保护作用可被CPT1抑制剂依托莫西复制。CPT1抑制通过降低聚（ADP-核糖）聚合酶1的表达，减少了心肌细胞中双特异性磷酸酶1的ADP核糖基化，导致p38丝裂原活化蛋白激酶磷酸化减少，并刺激心肌细胞增殖。我们目前的研究表明，逆转代谢重编程是刺激成体心肌细胞增殖的有效策略。CPT1是促进心脏再生和治疗心肌梗死的潜在治疗靶点。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3dfd/11873623/c6252d6a64fc/gr7.jpg
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