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.