Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
J Cardiovasc Pharmacol. 2021 Feb 1;77(2):142-152. doi: 10.1097/FJC.0000000000000952.
Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate, are indispensable for isoprenylation by serving as donors of a prenyl moiety to small G proteins. In the human body, isoprenoids are mainly generated by the mevalonate pathway (also known as the cholesterol-synthesis pathway). The hydroxymethylglutaryl coenzyme A reductase catalyzes the first rate-limiting steps of the mevalonate pathway, and its inhibitor (statins) are widely used as lipid-lowering agents. In addition, the FPP synthase is also of critical importance for the regulation of the isoprenoids production, for which the inhibitor is mainly used in the treatment of osteoporosis. Synthetic FPP can be further used to generate geranylgeranyl pyrophosphate and cholesterol. Recent studies suggest a role for isoprenoids in the genesis and development of cardiovascular disorders, such as pathological cardiac hypertrophy, fibrosis, endothelial dysfunction, and fibrotic responses of smooth-muscle cells. Furthermore, statins and FPP synthase inhibitors have also been applied for the management of heart failure and other cardiovascular diseases rather than their clinical use for hyperlipidemia or bone diseases. In this review, we focus on the function of several critical enzymes, including hydroxymethylglutaryl coenzyme A reductase, FPP synthase, farnesyltransferase, and geranylgeranyltransferase in the mevalonate pathway which are involved in regulating the generation of isoprenoids and isoprenylation of small GTPases, and their pathophysiological role in the cardiovascular system. Moreover, we summarize recent research into applications of statins and the FPP synthase inhibitors to treat cardiovascular diseases, rather than for their traditional indications respectively.
异戊烯化是小 GTP 酶激活和功能所必需的重要转录后修饰。异戊烯基，包括法呢基焦磷酸（FPP）和香叶基焦磷酸，是小 G 蛋白异戊烯化所必需的，它们作为异戊烯基供体。在人体内，异戊烯基主要通过甲羟戊酸途径（也称为胆固醇合成途径）生成。羟甲基戊二酰辅酶 A 还原酶催化甲羟戊酸途径的第一个限速步骤，其抑制剂（他汀类药物）被广泛用作降脂药物。此外，FPP 合酶对于异戊烯基的产生的调节也至关重要，其抑制剂主要用于治疗骨质疏松症。合成的 FPP 可进一步用于生成香叶基焦磷酸和胆固醇。最近的研究表明，异戊烯基在心血管疾病的发生和发展中起作用，如病理性心肌肥厚、纤维化、内皮功能障碍和平滑肌细胞的纤维反应。此外，他汀类药物和 FPP 合酶抑制剂也已用于心力衰竭和其他心血管疾病的治疗，而不是其在高脂血症或骨骼疾病中的临床应用。在这篇综述中，我们重点介绍了几种关键酶，包括羟甲基戊二酰辅酶 A 还原酶、FPP 合酶、法尼基转移酶和香叶基转移酶在甲羟戊酸途径中的作用，这些酶涉及调节异戊烯基的产生和小 GTP 酶的异戊烯化，以及它们在心血管系统中的病理生理作用。此外，我们总结了最近关于他汀类药物和 FPP 合酶抑制剂应用于治疗心血管疾病的研究，而不是分别用于其传统适应证。
