Abstract
Atherosclerosis is the main cause of cardiovascular diseases which in turn, lead to the highest number of mortalities globally. This pathophysiological condition is developed due to a constant elevated level of plasma cholesterols. Statin is currently the widely used treatment in reducing the level of cholesterols, however, it may cause adverse side effects. Therefore, there is an urgent need to search for new alternative treatment. PCSK9 is an enzyme responsible in directing LDL-receptor (LDL-R)/LDL-cholesterols (LDL-C) complex to lysosomal degradation, preventing the receptor from recycling back to the surface of liver cells. Therefore, PCSK9 offers a potential target to search for small molecule inhibitors which inhibit the function of this enzyme. In this study, a marine invertebrate Acanthaster planci, was used to investigate its potential in inhibiting PCSK9 and lowering the levels of cholesterols. Cytotoxicity activity of A. planci on human liver HepG2 cells was carried out using the MTS assay. It was found that methanolic extract and fractions did not exhibit cytotoxicity effect on HepG2 cell line with IC50 values of more than 30 µg/mL. A compound deoxythymidine also did not exert any cytotoxicity activity with IC50 value of more than 4 µg/mL. Transient transfection and luciferase assay were conducted to determine the effects of A. planci on the transcriptional activity of PCSK9 promoter. Methanolic extract and Fraction 2 (EF2) produced the lowest reduction in PCSK9 promoter activity to 70 and 20% of control at 12.5 and 6.25 μg/mL, respectively. In addition, deoxythymidine also decreased PCSK9 promoter activity to the lowest level of 60% control at 3.13 μM. An in vivo study using Sprague Dawley rats demonstrated that 50 and 100 mg/kg of A. planci methanolic extract reduced the total cholesterols and LDL-C levels to almost similar levels of untreated controls. The level of serum glutamate oxalate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) showed that the administration of the extract did not produce any toxicity effect and cause any damage to rat liver. The results strongly indicate that A. planci produced a significant inhibitory activity on PCSK9 gene expression in HepG2 cells which may be responsible for inducing the uptake of cholesterols by liver, thus, reducing the circulating levels of total cholesterols and LDL-C. Interestingly, A. planci also did show any adverse hepato-cytotoxicity and toxic effects on liver. Thus, this study strongly suggests that A. planci has a vast potential to be further developed as a new class of therapeutic agent in lowering the blood cholesterols and reducing the progression of atherosclerosis.
Highlights
This article is an open access articleAtherosclerosis is known as a major risk of cardiovascular disease (CVD) [1]
The results obtained from this study clearly indicate that the extract and fractions prepared from A. planci as well as an isolated compound deoxythymidine, were not cytotoxic on HepG2 cells and considered as safe to be used to determine the effects on proprotein convertase subtilisin kexin 9 (PCSK9) gene expression
The results strongly suggest that the methanolic extract of A. planci contained promising small molecule inhibitors that produced a significant effect in decreasing the levels of total cholesterol and low-density lipoprotein-cholesterols (LDL-C) in rats that were previously fed with high fat diet via PCSK9 inhibition
Summary
This article is an open access articleAtherosclerosis is known as a major risk of cardiovascular disease (CVD) [1]. The formation and progression of atherosclerotic plaque are induced initially by the subendothelial deposition of oxidized low-density lipoprotein-cholesterols (LDL-C) which triggers the uptake of cholesterols by macrophages, which in turn, transformed into lipid-loaded foam cells [4]. These foam cells are responsible for inducing a cascade of inflammatory responses which include accumulation of additional LDL-C and extracellular matrices which lead to the build-up of plaque inside the walls of arteries [5]. As the arteries hardened and narrowed due to the accumulation and advanced formation of plaques that protrude into the lumen of blood vessels, the blood flow to the vital organs such as heart and brain is impeded which eventually causes the life-threatening CVD such as heart attack and stroke [6]
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