Pravastatin sodium is a reversible competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, with an IC50 of 5.6μM. Pravastatin sodium is commonly used in the research of hypercholesterolemia and various cardiovascular diseases[1]. HMG-CoAR is located in the cytoplasm of eukaryotic cells and some prokaryotes. The enzyme utilizes NADPH to reduce HMG-CoA to mevalonate, serving as the rate-limiting enzyme in the first stage of cholesterol biosynthesis. Critical catalytic residues of this enzyme include Lys691, Glu559, Asp767, and His866[2]. Pravastatin sodium binds to the pocket of HMG-CoAR where HMG-CoA would bind, through van der Waals forces, thereby reducing the synthesis of cholesterol[3].
In vitro, treatment with Pravastatin sodium (1μg/mL) alleviates high glucose-induced migration dysfunction in cytotrophoblast (CTB) cells incubated at varying glucose concentrations [4]. Treatment of endothelial colony-forming cells (ECFCs) with Pravastatin sodium (0-2000μM) significantly enhances cell proliferation, migration, and tube formation capabilities.Pravastatin sodium increases the phosphorylation of protein kinase B (AKT) and endothelial nitric oxide synthase (eNOS), as well as the expression levels of heme oxygenase-1 (HO-1), vascular endothelial growth factor A (VEGF-A), and placental growth factor (PlGF). Pravastatin sodium decreases the expression levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelial protein C receptor (Eng) [5].
In vivo, oral administration of Pravastatin sodium (20mg/kg/day) to diabetic rats for 8 weeks resulted in an increase in body weight. Pravastatin sodium significantly reduced the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase, thereby improving liver enzyme abnormalities caused by diabetes. Pravastatin sodium also decreased fasting blood glucose levels and increased hepatic glycogen content [6]. Oral treatment with Pravastatin sodium (20mg/kg/day) for 14 days in mice with cardiac fibrosis induced by isoproterenol led to a reduction in CK-MB, serum triglycerides, collagen I and III levels in heart tissue, cardiac inflammatory cells, and cardiac fibrosis levels [7].
References:
[1] Raasch RH. Pravastatin sodium, a new HMG-CoA reductase inhibitor. DICP. 1991 Apr;25(4):388-94.
[2] Miziorko HM. Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys. 2011 Jan 15;505(2):131-43.
[3] Istvan ES. Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Am Heart J. 2002 Dec;144(6 Suppl):S27-32.
[4] Pantho AF, Mohamed S, Govande JV, et al. Pravastatin Protects Cytotrophoblasts from Hyperglycemia-Induced Preeclampsia Phenotype. Cells. 2024 Sep 13;13(18):1534.
[5] Meyer N, Brodowski L, Richter K, et al. Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro. J Clin Med. 2021 Jan 6;10(2):183.
[6] Kaya HK, Demirtas B, Yokus B, et al. Comparative effects of pravastatin and rosuvastatin on carbohydrate metabolism in an experimental diabetic rat model. Acta Pharm. 2024 Mar 30;74(1):117-130.
[7] Rana A, Singh TU, Sharma M, et al. Pravastatin attenuates isoprenaline induced cardiac fibrosis in a mouse model. Biotech Histochem. 2023 Nov;98(8):567-577.
Pravastatin sodium 是一种HMG-CoA可逆的竞争性抑制剂，IC50为5.6μM，通常用于高胆固醇血症和冠心病的研究[1]。HMG-CoAR存在于真核生物和一些原核生物的细胞质中。HMG-CoAR利用NADPH将HMG-CoA还原为甲羟戊酸，是介导胆固醇生物合成第一阶段的限速酶，关键的催化残基是Lys691、Glu559、Asp767和His866[2]。Pravastatin sodium通过范德华力占据HMG-CoAR与HMG-CoA结合的结合口袋，从而降低胆固醇的合成[3]。
在体外，Pravastatin sodium（1μg/mL）处理不同葡萄糖浓度孵育的细胞滋养层（CTB）细胞，减轻了高血糖诱导的CTB 迁移功能障碍[4]。Pravastatin sodium（0-2000μM）处理内皮集落形成细胞（ECFC），显著增强了细胞的增殖、迁移和管形成能力，增加了蛋白激酶 B（AKT）和内皮一氧化氮合酶（eNOS）的磷酸化和血红素加氧酶-1（HO-1）、血管内皮生长因子 A （VEGF-A）和胎盘生长因子 （PlGF）的表达水平，但降低了可溶性 fms 样酪氨酸激酶-1（sFlt-1）和内皮糖蛋白（Eng）的表达水平[5]。
在体内，Pravastatin sodium（20mg/kg/day）通过口服治疗糖尿病大鼠8周，Pravastatin sodium虽然增加了糖尿病大鼠的体重，但是显著降低了糖原磷酸化酶、乳酸脱氢酶和葡萄糖-6-磷酸酶水平改善了糖尿病引起的肝酶不良反应，并降低空腹血糖水平，增加肝糖原含量[6]。Pravastatin sodium（20mg/kg/day）通过口服治疗通过异丙肾上腺素诱导的心脏纤维化小鼠14天，降低了CK-MB、血清甘油三酯、心脏组织胶原蛋白 I 和 III 水平、心脏炎症细胞和心脏纤维化水平[7]。