Statins : More than Cholesterol Reduction

This article contains information from a talk given by the author at the RMS on 14/01/03, entitled: Statins and Immuno-modulation: A New Frontier. Statins represent one of the major successes of cardiology in the secondary prevention of coronary artery disease. This article attempts to understand the very molecule which makes many quake in their boots, cholesterol, and how basic science research continues to find novel methods in which statin therapy can participate. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service url: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: ISSN 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, Summer 2003 : 24-27 doi:10.2218/resmedica.v0i0.1010 Statins: More than Cholesterol Reduction Rameen Shakur BA (Hons) MPhil (Cantab.) Introduction. This article contains information from a talk given by the author at the RMS on 14/01/03, en­ titled: Statins and Immuno-modulation: A New Frontier. Statins repre­ sent one of the major successes of cardiology in the secondary preven­ tion of coronary artery disease. This article at­ tempts to understand the very molecule which makes many quake in their boots, cholesterol, and how basic science research continues to find novel methods in which statin therapy can participate. Large scale epidemiological studies in the gen­ eral population, especially through the Framingham Heart study, the largest and most comprehensive medical study in the history of cardiology and some would say in modem day epidemiology, has identified several risk factors pertinent to the development of cardiovascular disease. The study based in the small town of Framingham on the outskirts of Boston, Massa­ chusetts in the USA, has provided the means for risk assessment and public health targets in the prevention of coronary artery disease. Some of these risk factors for coronary artery disease in­ clude age, hypertension, hypercholesterolaemia, diabetes, and cigarette smoking '. However, one factor that has proved to be, and continues to be, one of the great successes of 21st century medi­ cine has been the introduction of the HMG-CoA reductase inhibitors. Yet, to better comprehend this “magic drug” one has to appreciate the drug’s target, that of cholesterol. Cholesterol. Cholesterol is a ubiquitous alicyclic compound, a member of the lipid family, which is distributed in both free and esterified forms throughout the body. Cholesterol can exist in a number of different structural isomers, from having a single hydroxyl group at C-3 to having an unsaturated centre between the C5 and C-6 atoms (see figure 1). Physically, cholesterol like other lipids is hydrophobic except for a single hydrophilic OH group, attached to which are several hydrophobic rings. Given the hydrophobic nature of cholesterol, it is therefore surprising that the concentration of cholesterol in the plasma of healthy people is usually 150-200mg d L 1. The high level of solubility of cholesterol in blood is attributed to the formation of protein-lipid com­ plexes, called lipoproteins (ie. LDL and VLDL) which through the aid of apo-lipoproteins are able to bind and hence dissolve large amounts of cho­ lesterol within blood. Physiologically, approxi­ mately 30% of the total circulating cholesterol in the human body occurs as free cholesterol, whilst the remainder exists as cholesterol esters attached to plasma lipoproteins. Cholesterol is a vital biological molecule, play­ ing an essential role in the architecture of the cell membrane, by providing rigidity but also flu­ idity for the flipping of lipids on the cell mem­ brane. Cholesterol is also the precursor for the steroid hormones such as the sex hormones Oes­ trogen and Testosterone, and the corticoand mineralocorticosteroids such as cortisol and al­ dosterone respectively. Cholesterol is also Figure 1. The chemical structure o f Cholesterol. “Currently the most potent treatment for hyperlipidaemia are the HMG-CoA reductase inhibitors or statins.”


Statins: More than Cholesterol Reduction
Rameen Shakur BA (Hons) MPhil (Cantab.)Introduction.This article contains information from a talk given by the author at the RMS on 14/01/03, en titled: Statins and Immuno-modulation: A New Frontier.Statins repre sent one of the major successes of cardiology in the secondary preven tion of coronary artery disease.This article at tempts to understand the very m olecule w hich makes many quake in their boots, cholesterol, and how basic science research continues to find novel methods in which statin therapy can participate.
Large scale epidemiological studies in the gen eral population, esp ecially through the Framingham Heart study, the largest and most comprehensive medical study in the history of cardiology and some would say in modem day epidemiology, has identified several risk factors pertinent to the development of cardiovascular disease.The study based in the small town of Framingham on the outskirts of Boston, Massa chusetts in the USA, has provided the means for risk assessment and public health targets in the prevention of coronary artery disease.Some of these risk factors for coronary artery disease in clude age, hypertension, hypercholesterolaemia, diabetes, and cigarette smoking '.However, one factor that has proved to be, and continues to be, one of the great successes of 21st century medi cine has been the introduction of the HMG-CoA reductase inhibitors.Yet, to better comprehend this "magic drug" one has to appreciate the drug's target, that of cholesterol.

Cholesterol.
Cholesterol is a ubiquitous alicyclic compound, a member of the lipid family, which is distributed in both free and esterified forms throughout the body.Cholesterol can exist in a number of different structural isomers, from having a single hydroxyl group at C-3 to having an unsaturated centre between the C5 and C-6 atoms (see figure 1).Physically, cholesterol like other lipids is hydrophobic except for a single hydrophilic OH group, attached to which are several hydrophobic rings.
Given the hydrophobic nature of cholesterol, it is therefore surprising that the concentration of cholesterol in the plasma of healthy people is usually 150-200mg d L 1.The high level of solubility of cholesterol in blood is attributed to the formation of protein-lipid com plexes, called lipoproteins (ie.LDL and VLDL) which through the aid of apo-lipoproteins are able to bind and hence dissolve large amounts of cho lesterol within blood.Physiologically, approxi mately 30% of the total circulating cholesterol in the human body occurs as free cholesterol, whilst the remainder exists as cholesterol esters attached to plasma lipoproteins.
Cholesterol is a vital biological molecule, play ing an essential role in the architecture of the cell membrane, by providing rigidity but also flu idity for the flipping of lipids on the cell mem brane.Cholesterol is also the precursor for the steroid hormones such as the sex hormones Oes trogen and Testosterone, and the cortico-and mineralocorticosteroids such as cortisol and al dosterone respectively.Cholesterol is also "Currently the most potent treatment for hyperlipidaemia are the HMG-CoA reductase inhibitors or statins."abundant in bile salts, allowing the process of emulsification for fat metabolism.

C h o le ste ro l S y n th e sis -The M e va lo n a te Pathway.
The derivation of cholesterol can either be through diet or through de novo biosynthesis, which accounts for 45% of the cholesterol in the body.Whilst biosynthesis in the liver and the small intestines accounts for 10% and 15% respectively; other major synthetic sites include the adrenal cortex and reproductive tissues.The synthesis of cholesterol occurs in the cytoplasm and results from the reduction of the high energy bonds of ATP and Acetyl-CoA (ACT-CoA).As the pre-cursor in the cholesterol pathway ACT-CoA is converted to mevalonate via the formation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).This critical early step is rate-limiting in cholesterol synthesis and is regulated by the enzyme HMG-CoA reductase.
Upon successive phosphorylations of mevalonate and its intermediates an activated isoprenoid molecule, Isopentenyl Pyrophosphate, (IPP) is produced.Through the subsequent condensations of IPP to famesyl pyrophosphate (FPP), and through the catalysis of the NADPHrequiring enzyme, squalene synthase, squalene is produced.It is the cyclisation of squalene to Lanosterol that produces the end product of cholesterol.

Cholesterol regulation.
The level of cholesterol synthesis can in part be regulated through the dietary intake of cholesterol and so the cellular level of cholesterol is maintained through the following independent but interacting mechanisms: 1) Cholesterol levels act as a negative feedback inhibitor for HMG-CoA reductase.Additionally, during times of excess, there is decreased expression of the HMG-CoA reductase gene resulting in low levels of mRNA for translation of HMG-CoA reductase.
2) The activity of HMG-CoA reductase is varied through covalent modification.This is achieved through either phosphorylating or dephosphorylating the enzym e, w hereby phosphorylation of the enzyme reduces its activity.Phosphorylation is stimulated in context to the levels of cAMP in the body, under the hormonal control of insulin and glucagon.Increases in cAMP lead to the activation of the cAMP-dependent protein kinase, PKA, which in turn results in the phosphorylation and an increase in the activity of the phosphoprotein phosphatase inhibitor-1 (PPI-1).PPI-1 inhibits the activity of numerous phosphatases of which HMG-CoA reductase is one.It is through this method that hormones such as insulin, which causes a decrease in cAMP levels, leads to the activation of cholesterol synthesis.
3) Finally, both LDL and HDL receptor-mediated transport can also regulate plasma cholesterol levels.This process is based on the active uptake of excess hepatic cholesterol from the liver into the serum through LDL .Cholesterol in plasma membranes can be later extracted and esterified by HDL in the peripheral tissues.Cholesterol is finally excreted in the bile either in the form of bile salts or as free cholesterol.

HMG-CoA reductase inhibitors -Statins.
C urrently the m ost potent treatm ent for hyperlipidemia are the HMG-CoA reductase inhibitors or statins.In 2000, statins were the sec ond most popular drug in terms of sales , with sales of $15.9 billion -up 21% from 1999.2 Statins are HMG-CoA reducatase inhibitors, inhibiting the rate limiting enzyme HMG-CoA reducatase which conducts the breakdown of HMG-CoA to mevalonate, vital for the synthe sis of cholesterol and isoprenoids further down stream in the pathway.Statins are used extensively in current medical practice as a proven method of lowering blood lipid levels.Through numerous clinical trials this class of drugs have demonstrated their benefit in greatly reducing cardiovascular morbidity and mortality, as well as in the primary and second ary prevention of coronary disease in patients with and without coronary artery disease 3-9.In addition to these clinical trials further in vitro and in vivo findings suggest that statins, through their highly effective lipid lowering abilities have other pleiotropic effects, in particular anti-inflammatory properties.3

Statins: Anti-inflammatorv Properties.
An association between statin treatment and an anti-inflammatory response can be defined from m arkers o f acute inflam m ation, including cytokines, C reactive protein (CRP) and white cell count.Needless to say, all the above factors are also indicative of being in a higher coronary risk factor group10.
Further analysis into the schematic scenario of the atherosclerotic process allowed a definite conclusion that the evolution of atherosclerotic lesions involves an interaction between four major cell types: endothelial cells (ECs), smooth m uscle cells (SM C s), m acrophages, and lymphocytes.It has since been suggested that statins may interfere directly with several key mechanisms necessary for the involvement of different cellular elements in all the steps of atherogenesis.
production within vascular endothelial cells12.
Atherosclerosis over vascular endothelium having activated the endothelium has also been shown to increase the expression of adhesion molecules such as ICAM-1, VCAM-1 and Eselectin , vital for the extrav asatio n of leuokocytes.Using a rat model Katoh et al. 13 showed how a particular statin (Fluvastatin) can reduce the expression of soluble ICAM-1.This result was also seen in hypercholesterolaemic patients, where there was also a reduction in the level of soluble P-selectin14.In addition statins have also been shown to inhibit the monocyteendothelial interaction stimulated by oxidised LDL15.It is thought that oxidised LDL is able to be chemotactic for monocytes and human T lymphocytes16, through inducing the expression o f factors such as MCP-1 by both human endothelial cells and smooth muscle cells 17.

The effect o f Statins on endothelial function.
S ince the observ atio n th at end o th elial dysfunction arises early in the presence of elevated cholesterol levels11 several experimental studies began to explore the effects of statins on preserving endothelial function.As a result it has shown that statins can alter the bioavailability of nitric oxide (NO) through the posttranslational up regulation of endothelial NO synthase (eNOS) mRNA and the decrease of superoxide anion production within vascular endothelial cells.1

The effect of Statins on T-cell function.
It has been demonstrated that statins inhibited the Interferon-g (IFN-g)-mediated induction of class II major histocompatibility complexes (MHC II) on antigen presenting cells, including hum an m onocytes/m acrophages 18. M ore recently, evidence by Weitz-Schmidt has also indicated that the statins L ovastatin and mevastatin selectively block the lymphocyte function associated antigen-1 (LFA-1).LFA-1 is involved in the adhesion of leukocytes to the As research continues into these and the other pleiotropic effects of statins, we can expect a new generation of cholesterol reduction drugs which are able to target a number of the secondary downstream products in the mevalonate pathway, which play an integral part in the inflammatory process.
The author has no conflict o f interest, no fi nancial support from the pharm aceutical in dustry. References.

Figure 1 .
Figure 1.The chemical structure o f Cholesterol.
Figure 2. The Cholesterol synthesis pathway.

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