Pathogenesis of atherosclerosisand the role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

doi:10.1016/S0002-9149(05)80011-6

The American Journal of Cardiology

Volume 76, Issues 1–2, Supplement 1, 13 July 1995, Pages 21A-28A

https://doi.org/10.1016/S0002-9149(05)80011-6 Get rights and content

Abstract

Atherosclerosis is a complex multifactorial process resulting from an excessive inflammatory/fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesion present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring within the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention. in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis—and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation; hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, this group provided in vitro and in vivo evidence of decreases in SMC proliferation by fluvastatin and simvastatin, but not pravastatin, independent of their cholesterol-lowering properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70–90% decrease) was completely prevented by the addition of mevalonate, and partially prevented (70–80%) by famesol or geronylgeraniol. This confirms the specific role of isoprenoid metabolites—most probably geronylgerylated protein(s)—in regulating cell migration and proliferation. The inhibitory effect of fluvastatin and simvastatin on cholesterol esterification induced by acetyl low density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol. Taken together, these data support the importance of pharmacologic modulation of the mevalonate pathway in controlling major events involved in atherogenesis.

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Lovastatin dose-dependently inhibited TSP-1-induced chemotaxis, which was reversed by mevalonate. Mevalonate did not induce chemotaxis independently. FTI and FPT, but not GGTI or Y-27632, inhibited TSP-1-induced Ras activation and TSP-1-induced chemotaxis. Lovastatin inhibition of Ras activation was reversed with mevalonate.
Ras, not Rho, is relevant for TSP-1-induced VSMC chemotaxis. These data suggest that lovastatin suppresses TSP-1-induced chemotaxis by inhibition of Ras.
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With the above data suggesting a potential reduction in major morbidity and mortality in both the cardiac ischemia and the noncardiac ischemia surgical populations with the use of statins for both short-term and long-term therapy, the question of mechanism of this effect is raised and clearly suggests that more than one mechanism is at play. Although it is well recognized that the primary mechanism of statins is as a reversible HMG-CoA reductase inhibitor, which reduces the levels of mevalonic acid and induces up regulation of low-density lipoprotein (LDL) receptor expression and ultimately lowers LDL levels in the blood, this is postulated to be only one of many beneficial effects of statins [19–23]. It is well recognized that this effect takes prolonged treatment with statins and is most relevant in the hyperlipidemic cardiac ischemia population.
The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors (statins) in patients undergoing coronary artery bypass grafting have been recognized. Reduced mortality rates and clinical events have been demonstrated. These outcomes were examined in patients taking statins who underwent cardiac valve operations.
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The statin group had more comorbidities. Although they had increased risk factors, including previous stroke (30 of 203 vs 16 of 244, p = 0.004), diabetes (66 of 203 vs 32 of 244, p < 0.0001), cerebrovascular disease (45 of 203 vs 24 of 244, p = 0.003), and dyslipidemia (191 of 203 vs 63 of 244, p < 0.0001), they had better outcomes. The unadjusted odds ratio (OR) for the composite end point of death/stroke/renal failure was 1.90 (95% confidence interval [CI], 0.95 to 3.76; p = 0.068) favoring the statin group. By univariate analysis, the adjusted OR for the composite end point demonstrated a benefit with statin therapy: diabetes, 2.29 (95% CI, 1.16 to 4.71; p = 0.024); stroke, 2.15 (95% CI, 1.06 to 4.35; p = 0.034); and renal dysfunction, 2.05 (95% CI, 1.02 to 4.13; p = 0.045).
Statin therapy in this population undergoing cardiac valve procedures was associated with decreased postoperative morbidity and death. The mechanism may be independent of statins' lipid-lowering effects. A prospective, randomized-control trial of statin therapy in this population is warranted.
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Statins are powerful agents for lowering plasma cholesterol levels, which act by inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase. Evidence suggests that some of the beneficial effects may depend on their anti-inflammatory properties, due to their ability to suppress the synthesis of isoprenoids. The present study analyzes the effects of short-term simvastatin exposure on monocyte migration, cell adhesion, and endothelial cytoskeleton. We demonstrate that simvastatin completely inhibited the migration of THP-1 monocytic cells after 24 h of incubation, being prevented by coincubation with mevalonate (MVA) and geranylgeranylpyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Simvastatin decreased chemotaxis to 70% after one hour of incubation; surprisingly neither MVA, GGPP nor FPP were able to restore the effects of the drug. Simvastatin also significantly reduced the adhesion of monocytes to interleukin-1β (IL-1β)-activated endothelium to 80% after preincubation for 24 h. This effect was completely reversed by coincubation with MVA and GGPP, and partially with FPP. Unexpectedly, simvastatin increased adhesion molecules expression VCAM-1 and ICAM-1 on cytokine-stimulated endothelial cells. Examination of the actin cytoskeleton on IL-1β-activated endothelial cells showed that both 4 and 24 h of incubation with simvastatin produced a complete disappearance of F-actin, being completely restored by MVA and partially by GGPP and FPP after 24 h of coincubation. We suggest that cytoskeleton disorganization in endothelial cells is important for inhibiting monocyte adhesion, altering the adhesion molecules function. Taken together, these results strongly support the beneficial anti-inflammatory properties of statins, contributing to the overall clinical effects.
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Pathogenesis of atherosclerosisand the role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

Abstract

Am Heart J

J Am Coll Cardiol

J Biol Chem

J Biol Chem

Artherosclerosis

J Lipid Res

Atherosclerosis

Atherasclerosis

Biochim Biophys Acta

J Biol Chem

Pharrn Res

Atherosclerosis

Atherosclerosis

J Biol Chem

Trends Biochem Sci

J Lipid Res

J Biol Chem

J Am Coll Cardiol

Biochim Biophys Acta

Metabolism

An update coronary risk profile. A statement for health professionals

Circulation

Second report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel II)

Circulation

Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease

Circulation

Update on the pathogenesis of atherosclerosis

Am J Med

The pathogenesis of atherosclerosis: a perspective for the 1990s

Nature

A modern view of atherogenesis

Am J Cardiol

Human Atherosclerosis. III. Immunocytochemical analysis of the cell composition of lesions of young adults

Am J Pathol

Coronary atherosclerosis. A multifactorial disease

Circulation

A receptor-mediated pathway for cholesterol homeostasis

Science

Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity

N Engl J Med

Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis

Annu Rev Biochem

Macrophage scavenger receptors

Curr Opin Lipidol

Regulation of smooth muscle cell growth injured artery

J Cardiovasc Pharmacol

The contribution of studies of atherosclerotic lesions in young people to future research

Ann NY Acad Sci