Cardiac decompensation and promiscuous prenylation of small GTPases in cardiomyocytes in response to local mevalonate pathway disruption.
Cardiac decompensation and promiscuous prenylation of small GTPases in cardiomyocytes in response to local mevalonate pathway disruption.
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DOI：
10.1002/path.5837
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Brody MJ
中科院分区：
文献类型：
--
作者：
Essandoh K;Auchus RJ;Brody MJ
对主要甲羟戊酸途径酶的研究已经证明了局部类异戊二烯合成在心脏稳态中的重要性。法呢基二磷酸合酶（FPPS）合成胆固醇生物合成和蛋白质异戊二烯化所需的类异戊二烯前体。Wang等，在最近发表在病理学杂志上的一篇文章中，优雅地阐明了心肌细胞中FPPS缺陷的病理结果，这矛盾地导致小GTP酶Ras和Rheb的异戊烯化增加。心肌细胞FPPS耗竭导致严重的扩张型心肌病，这与脂化蛋白富集的心脏组分中增强的GTP负载和Ras和Rheb的丰度以及下游肥大性ERK 1/2和mTOR信号通路的强烈激活相关。抑制法尼基转移酶可改善心肌病以及因FPPS缺失而引起的ERK 1/2和mTOR激活，这表明FPPS活性受损通过法尼基转移酶的非经典作用导致Ras和Rheb的混杂激活。在这里，我们讨论的结果和适应性信号机制，以响应局部心肌细胞甲羟戊酸途径活动的中断，突出如何在甲羟戊酸途径的一个关键分支点的改变影响心脏生物学和功能和干扰蛋白质异戊烯化，这可能会揭示新的战略和复杂的靶向甲羟戊酸途径治疗心血管疾病。
Investigations of major mevalonate pathway enzymes have demonstrated the importance of local isoprenoid synthesis in cardiac homeostasis. Farnesyl diphosphate synthase (FPPS) synthesizes isoprenoid precursors needed for cholesterol biosynthesis and protein prenylation. Wang et al., in a recently published article in the Journal of Pathology, elegantly elucidated the pathological outcomes of FPPS deficiency in cardiomyocytes, which paradoxically resulted in increased prenylation of the small GTPases, Ras and Rheb. Cardiomyocyte FPPS depletion caused severe dilated cardiomyopathy that was associated with enhanced GTP-loading and abundance of Ras and Rheb in lipidated protein-enriched cardiac fractions and robust activation of downstream hypertrophic ERK1/2 and mTOR signaling pathways. Cardiomyopathy and activation of ERK1/2 and mTOR caused by loss of FPPS were ameliorated by inhibition of farnesyltransferase, suggesting that impairment of FPPS activity results in promiscuous activation of Ras and Rheb through non-canonical actions of farnesyltransferase. Here, we discuss the findings and adaptive signaling mechanisms in response to disruption of local cardiomyocyte mevalonate pathway activity, highlighting how alteration in a key branch point in the mevalonate pathway affects cardiac biology and function and perturbs protein prenylation, which might unveil novel strategies and intricacies of targeting the mevalonate pathway to treat cardiovascular diseases.
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