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Mechanistic insights into the acute cardiovascular protection of Atorvastatin

Shakkotai, P.V.; (2011) Mechanistic insights into the acute cardiovascular protection of Atorvastatin. Doctoral thesis, UCL (University College London). Green open access

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Abstract

Coronary artery disease is by far the single biggest killer in the UK. Atherosclerosis is the underlying cause of coronary artery disease. Hypercholesterolemia is one of the major risk factors in the aetiopathogenesis of atherosclerosis. 3-Hydroxy Methyl Glutaryl CoA reductase (HMG CoA) inhibitors, known as statins, reduce cholesterol levels and offer mortality and morbidity benefit for those with coronary artery disease.The cardiovascular benefits from statins tend to be significant even in individuals with normal cholesterol levels which suggests that there are non-lipid lowering benefits of statins termed “pleiotropic” effects. Statins attenuate infarct size expansion due to lethal reperfusion injury either prior to ischaemia or at the onset of reperfusion by activating the pro-survival, Reperfusion Injury Salvage Kinase (RISK) pathway. As the duration of treatment acutely at the onset of reperfusion is too short to make any impact on cholesterol levels, it was hypothesized that the protection observed is due to a pleiotropic effect of the statins. The mechanism by which statins activate the RISK pathway is not entirely clear. Thus experiments with Langendorf perfused isolated rat heart preparation were used to obtain insights into potential mechanisms for statin’s pleiotropic effects in the setting of ischaemia-reperfusion by using Atorvastatin. Infarct size analysis and Western blot analysis were performed to measure cellular injury and protein activation respectively. Atorvastatin was shown to produce a reduction in infarct size when administered acutely during reperfusion at a dose of 50 micromol/l. Atorvatstatin has affinity to the glucocorticoid receptor at levels comparable to potent glucocorticoids. Glucocorticoids have also been shown to activate pro survival kinases. It was thus hypothesized that the acute cardiovascular effects of Atorvastatin may also be mediated by the glucocorticoid receptor, and would be blocked in the presence of the glucocorticoid receptor antagonist, RU486. However studies undertaken demonstarted inconclusive results as RU486 was itself shown to be protective and it would appear that it worked by an alternative mechanism. Since it is known that pre-ischaemic delivery of Atorvastatin also activates adenosine, an agent known to be cardioprotective. It was hypothesized that Atorvastatin administered during reperfusion may also protect the heart by an adenosine-dependent mechanism. However, despite the infarct sparing action of preischaemic administration of Atorvastatin being confirmed to be dependent on adenosine binding to its receptor, the protection of Atorvastatin administered during reperfusion was shown to be independent of adenosine. Finally, the acute effects of statins are believed to be due to their action on the HMG CoA reductase enzyme which results in a decrease in mevalonic acid and isoprenyl intermediates.The isoprenyl intermediates such as Rho A, are inhibitors of the various components of the RISK pathway. We were able to demonstrate for the first time that mevalonic acid abrogates the infarct size reduction of Atorvastatin administered during reperfusion. Western blot analysis did not reveal a significant reduction in active Rho A levels, however there was a trend towards a reduction and this reflected in the infarct size studies. Although not conclusive, these results would suggest that the acute cardiovascular effects of Atorvastatin, when given at reperfusion, were due to its pleiotropic effects on Rho A.

Type:Thesis (Doctoral)
Title:Mechanistic insights into the acute cardiovascular protection of Atorvastatin
Open access status:An open access version is available from UCL Discovery
Language:English
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Cardiovascular Medicine

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