Last updated: March 17, 2019
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Description: Preferred language style: English(U.K.)
This essay should be written as a biomedical essay concentrating on the molecular mechanism of LDL leading to atherosclerotic disease.
This essay should be about 2000 words.
This essay should address the topic (LDL and atherosclerotic disease).
This essay should teach the reader something new, and deal with the latest research.
This essay should have the following style: 1. Introduction (briefly setting out what is to come); 2. Body of Text (must be subdivided into sections with subheadings, illustrated where appropriate with figures and with references cited in the text); 3. Conclusion (brief summary of the main arguments that have been put).
This essay should use the Harvard system as the citation style, and should reference key points in the text, and list the sources of figures shown in the text, and references in the text should have an author where possible [just listing a web site is not enough].

 

 

 

 

 

 

 

 

Atherosclerotic disease is the main cause of mortality in the US and other developed nations, and is slowing becoming a problem in developing nations.  It is characterized by the formation of plaque that contains connective tissues matrix (such as collagen, proteoglycans, etc), smooth muscles, lipoproteins, the mineral calcium, inflammatory cells and newly-developed blood vessels (Shah, P.K., 2001).  Virchow, was the first the recognise the presence of cholesterol in atherosclerosis, which led to a greater interest in lipoproteins and the manner in which lipids are metabolised and transported (Benditt, E.P. et al, 1998).

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The exact manner and cause for atherosclerosis is not known.  However, many have suggested that it may be a long-standing inflammatory reaction following damage to certain blood vessels.  These agents tend to damage the inner-lining layer of cells (endothelium) and encourage deposition and retention of lipoproteins (Shah, P.K., 2001).

Atherosclerosis usually develops in the main blood vessel that arises from the heart (aorta) and the other blood vessels that supply the heart (coronary arteries), kidneys, central nervous system and the limbs.  These organs are at a higher risk of developing ischemic attack compared to the other sites in the body (Shah, P.K., 2001).

Studies demonstrate that the first step in the development of atherosclerosis is damage to the endothelium or its dysfunction, followed by infiltration and storage or retention of lipoproteins in the sub-epithelial space of the vessel wall.  Several risk factors for the development of endothelial dysfunction may be present and include higher LDL or VLDL levels, lower HDL levels, smoking (as the oxidation risk increases), diabetes mellitus, genetic defects, etc (Shah, P.K., 2001).

Some of the risk factors for the development of atherosclerosis include hypertension, increased cholesterol levels in the blood, smoking, diabetes mellitus, old age, sex, sedentary lifestyle, stress, etc (Benditt, E.P. et al, 1998).

Cholesterol is a fatty substance that has several important functions in the body.  Small amounts of cholesterol are required by the body to help form cell membrane (outer covering of the cells in the body), nerve cells and production of certain hormones (Astra Zeneca, 2003).  Cholesterol is transported in the body from the liver to the tissues and vice-versa, in combination with certain proteins and is known as ‘lipoproteins’.  Lipoproteins are of different types, based on their density or the manner in which they centrifuge, namely, Low-density lipoproteins (LDL), very-low density lipoproteins (VLDL) and high-density lipoproteins (HDL) (Astra Zeneca, 2003).

Cholesterol and other lipid (such as triglycerides) are insoluble, have a significant function in the cell membrane and can be a source of energy for the body. Cholesterol and other lipids require a specialised transport mechanism (Benditt, E.P. et al, 1998).

LDL (or commonly known as ‘bad cholesterol’) is a form in which the lipids are transported from the liver to the various cells and tissues of the body through the bloodstream.  LDL is associated with atherosclerosis, and hence the risk of developing various cardiovascular disorders is higher with an increased LDL level in the blood (Astra Zeneca, 2003).  In a normal adult, LDL accounts for 66% of the total blood cholesterol.  It is made up of 75% lipids and 25% proteins (Deodhare, S.G. et al, 2002).  High LDL levels in the blood can be caused due to consuming foodstuffs rich in cholesterol or having an inherited tendency to produce higher levels of LDL in the blood (Astra Zeneca, 2003).

HDL on the other hand (or ‘good cholesterol’) is a form in which the lipids are transported from various cells and tissues in the body to the liver for excretion from the body.  HDL helps to lower the risk of coronary heart disorders (Astra Zeneca, 2003) and protects the body from this condition (Edwards, C.R.W. et al, 1996).  HDL is composed of equal amounts of lipids and proteins (Deodhare, S.G. et al, 2002).

VLDL is made up by the liver from triglycerides, proteins and cholesterol.  It is made up of 90% lipids and 10% proteins (Deodhare, S.G. et al, 2002).

Cholesterol can also be derived from the diet through various foods obtained from animals such as meat, eggs, fish and dairy foods (Astra Zeneca, 2003).

The associated protein component of lipoproteins is known as ‘apoproteins’ which are of several types.  With relation to LDL, the apoprotein ‘Apo B’ is utilised.  The apoprotein component has several functions such as combining with the receptors to gain entry into the cell, making the lipid in the lipoprotein more soluble, and activating several mechanisms and enzymes required for lipid metabolism (Deodhare, S.G. et al, 2002).

LDL is discharged in 2 manners, namely, specific LDL receptor and non-macrophage activity (Deodhare, S.G. et al, 2002).

The majority of the LDL is disposed by the liver and other tissues by LDL-receptor medicated endocytosis (process by which the cell membrane invaginates to take up substances).  The remaining is disposed off through non-receptor techniques such as phagocytosis by mononuclear cells.  The LDL receptors present on the cell membrane combine with LDL.  The apoprotein and the receptor help in combining.  The macrophages take up the oxidised LDL by utilising scavenger receptors (Deodhare, S.G. et al, 2002).  When the LDL containing the cholesteryl ester is taken up by the cell into certain sac-like intra-cellular structures known as ‘vesicles’, through a receptor mediated pathway to give rise to an ‘endosome’.  The receptor and the endosome get separated, and the receptor arrives back at the cell membrane.  The cholesterol inhibits the activity of the endoplasmic reticulum and the HMG CoA reductase (in synthesis of cholesterol).  Cholesterol that is in excess amounts is converted into cholestryl esters and is stored in the vacuoles (Benditt, E.P. et al, 1998).

LDL contributes in many instances to the endothelial damage.  Several processes such as oxidation, aggregation, relation with proteoglycans, combination with immune substances, etc can bring about endothelial dysfunction (Shah, P.K., 2001).

LDL retained beneath the endothelium, cause progressive oxidation and are consequently swallowed by the macrophages through the use of certain scavenger receptors.  Swallowing or internalisation of LDL results in formation of lipid peroxides and permits storage of cholesterol esters, thus giving rise to foam cells (Cells containing fat droplets in their cytoplasm).  The extent to which LDL can be altered varies from one individual to another.  When LDL is modified and swallowed by the macrophages, the foam cells get activated and subsequently are damaged.  The other monocytes seem to be attracted to LDL by a process of chemotaxis.  The inflammatory process is extended by encouraging formation of converting monoctyes into macrophages and invasion of new monocytes into the atherosclerotic area.  Studies have shown that oxidised LDL is present in atherosclerotic lesions in both animal and human experiments.  Animal studies have shown that antioxidants and hypercholesterolemia can help to reduce the size of the atherosclerotic lesion (Shah, P.K., 2001).

Antioxidants prevent LDL from getting oxidised.  Vitamin E supplementation helps to reduce coronary heart disease.  Immune and inflammatory responses occur in atherosclerosis.  It consists of accumulation of monocyte-derived macrophages and certain types of T-lymphocytes.  The first type of lesion is known as ‘fatty streak’, containing monocyte derived macrophages and T-lymphocytes.   The inflammatory process may progress with increase in the macrophages and T-lymphocytes.  These cells may get activated and release certain substances that damage and cause degeneration of the tissues (necrosis).  This results in formation of a necrotic-lipid core in the plaque (Shah, P.K., 2001).

The atherosclerotic lesion is mainly composed of macrophages derived from foam cells. Studies have demonstrated that oxidised LDL is easily identified by the macrophages and internalised subsequently.  Most of the cells involved in the LDL process (such as the macrophages, endothelial cells, smooth muscles, etc) can oxidise LDL which then helps the macrophage receptor to identify it.  Free radicals are formed when the LDL gets oxidised by activated macrophage receptor present in the artery wall.  The free radicals contain energy and can cause injury to the smooth muscles on the endothelium (Deodhare, S.G. et al, 2002).

The mitochondria plays a very important role in cell signalling, thus helping to contribute to the manner of adapting to oxidative stress and initiation of several vascular disorders (Gutierrez, J. et al, 2006).  Mitochondrial dysfunction along with endothelial abnormalities plays a very important role in atherosclerosis.  Reactive oxygen is produced during the respiratory chain.  This could damage the mitochondrial lipids, enzymes and genetic material leading to severe dysfunction of the mitochondria.  Mitochondrial dysfunction can also develop in association with free cholesterol and oxidised LDL.  It has been demonstrated that individuals having mitochondrial dysfunction develop vascular disorders at a much earlier age, although the other risk factors for atherosclerosis might be absent (Puddu, P. et al , 2005).

In atherosclerotic lesions, the macrophages contain oxidised LDL products.  Studies are now being able to slowly prove that these oxidised lipoproteins tend to affect other processes that bring about atherosclerosis such as regulation of the blood vessels, inflammatory processes, immunological responses and clotting (Benditt, E.P. et al, 1998).

The oxidised LDL may activate the atherosclerosis by several mechanisms including direct endothelial damage, retention of the macrophages, formation of foam cells, smooth muscle cell damage and autoimmune action (Deodhare, S.G. et al, 2002).  In the sub-endothelial region of the arteries, LDL accumulates and is oxidised by several components such as the smooth muscles, endothelial cells and the macrophages.  This oxidised LDL brings about chemotaxis.  The monocytes transform into macrophages which phagocytose the oxidised LDL and are converted into foam cells.  Oxidised LDL can lead to dysfunction or damage of the endothelium along with degeneration (necrosis) of the foam cells, resulting in discharge of the degenerated material and enzymes (Deodhare, S.G. et al, 2002).

Recent studies have shown that oxidation of LDL makes it immunogenic in nature due to the development of neo-epitopes.  Certain substances that bring about an immunologic reaction, such as T-cell and B-cell epitopes are found in the oxidative LDL.  Individuals with certain inherited autoimmune conditions (such as higher plasma lp(a) and certain types of HLA antigens) are at a higher risk of developing autoimmune processes (Deodhare, S.G. et al, 2002).

The T-cells and macrophages may seem to have a harmful role in atherosclerosis, whereas B-cells seem to protect the body against the process.  Antibodies produced against the oxidised LDL can help to demonstrate the disease activity (Stoll, G. et al, 2006).

Oxidation of LDL is early process in the atherosclerosis mechanism, and later this oxidised LDL plays a role in the progression of the disease.  Studies conducted in the laboratory have demonstrated that oxidised LDL can help in the formation of foam cells.  Studies have also demonstrated that LDL undergoes significant oxidation in the blood cells.  In animals, the consumption of antioxidants led to a decrease in the atherosclerotic process (Stocker, R., 2004).

Recent studies have shown that oxidised LDL may cause inflammation of the vessel wall and may also result in certain autoimmune responses.  Individuals, who had suffered from heart attacks (myocardial infarction), were found to have LDL vulnerable to oxidation through laboratory studies.  This was directly associated with the extent to which coronary artery atherosclerosis developed evaluated through angiographs.  Another study showed that there was an increase in antibodies against oxidised LDL, which was directly related to disease of the carotid artery (Nilsson, J. et al , 1992).

Most of the evidences demonstrate that oxidation of LDL develops in the vessel wall.  The by-products of oxidation may encourage atherosclerosis by monocyte attraction and transformation into macrophages.  These macrophages are then able to internalise the oxidised LDL utilising scavenger receptors.  The by-products of oxidised LDL may be noxious and injure the endothelium (Goldman, L. et al, 2004).

The monocytes present in the tunica intima, can swallow the lipids and transform into foam cells or lipid-laden macrophage cells.  Often foam cells begin to multiply in the tunica intima brought out by a substance known as ‘macrophage-colony stimulating factor’.  Studies in mice having a lack of this substance, showed a decrease in development of atherosclerosis lesions.  Interleukin-3 and granulocyte-macrophage colony stimulatory factor also encouraged multiplication of the cells (Zipes, D.P., 2005).

The accumulated oxidised LDL in the arterial wall can play a major role in the development of inflammation.  Several immune reactions can develop, evident from animal studies conducted in this regard.  Antibody therapy seems to be viable in those in whom conventional therapy does not succeed (Nilsson, J. et al, 2006).

Many papers have suggested that the autoimmune and inflammatory processes play a very important role in the development and progression of atherosclerosis.  The disease can be monitored effectively and follow can be more successful by studying the inflammatory processes.  Using certain preventive strategies in controlling inflammation could be ideal in reducing atherosclerosis (Stoll, G et al, 2006). Further studies are required to help better understand the specific role of LDL in atherosclerosis, especially in human beings.

 

 

 

 

References:

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Deodhare, S.G. and Deodhare, S.S. (2002), General Pathology and Pathology of the Systems, 6th ed, Popular Prakashan, Bombay.

 

Edwards, C.R.W., Baird, J.D., Toft, A.D., Frier, B.M. and Shepherd, J. (1996), Endocrine and Metabolic Diseases, in: Edwards, C.R.W., Bouchier, I.A.D., and Haslett, C. (eds), Davidson’s Principles and Practice of Medicine, 17th Edition, Churchill Livingstone, Edinburgh.

 

Ginsberg, H.N. and Goldberg, I.J. (2001), Disorders of Lipoprotein Metabolism, in: Braunwald, E., Fauci, A., Kasper, D., Hauser, S., Longo, D., & Jameson, J. (eds). Harrison’s Principles of Internal Medicine, 16th Ed, McGraw-Hill, New York.

 

Goldman, L. and Ausiello, D. (2004), Cecil Textbook of Medicine, 22nd ed, Saunders, Philadelphia.

 

Gutierrez, J., Ballinger, S.W., Darley-Usmar, V.M. et al (2006), “Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells”, Circ Res, vol. 99, no. 9. 27th October, pp. 924-932. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17068300&query_hl=2&itool=pubmed_DocSum

 

Nilsson, J., Glazer, S. and Carlsson, R. (2006), “Antibodies against oxidized low-density lipoprotein for the treatment of vulnerable plaques”, Curr Opin Investig Drugs, vol. 7, no. 9, September, pp. 815-819.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed& cmd=Retrieve&dopt=AbstractPlus&list_uids=17002259&query_hl=8&itool=pubmed_DocSum

 

Nilsson, J., Regnstrom, J., Frostegard, J. et al (1992), “Lipid oxidation and atherosclerosis”, Herz, vol. 17, no. 5, October, pp. 263-269. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=1473812

 

Park, M.K. (2002), Park: Pediatric Cardiology for Practitioners, 4th ed, W.B. Saunders Company, Philadelphia.

 

 

 

Puddu, P., Puddu, G.M., Galletti, L. et al (2005), “Mitochondrial dysfunction as an initiating event in atherogenesis: a plausible hypothesis”, Cardiology, vol. 103, no. 3, 19th January. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15665536

 

Shah, P.K. (2001), Pathogenesis of arthrosclerosis, in: Rosendorff, C. (ed), Essential Cardiology: Principles and Practice, W.B. Saunders Company, Philadelphia.

 

Stocker, R. and Keaney Jr., J.F. (2004), “Role of oxidative modifications in atherosclerosis”, Physiol Rev, vol. 84, no. 4, October, pp. 1381-1478.

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Zipes, D.P., Libby, P., Bonow, R.O. (2005), Zipes: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed, W.B. Saunders Company, Philadelphia.

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