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Editorial [Hot Topic: Statin Biology Beyond Cholesterol Lowering: Hepatic Statins vs. Vascular Statins. (Guest Editor: Ryuichi Morishita) ]

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Abstract:

The prevalence of a high-cholesterol diet in many countries has brought about a marked increase in arteriosclerosis. Considering the current situation, treatment of hypercholesterolemia constitutes an important part of comprehensive strategies for the treatment of cardiovascular disease in the 21st century. Fortunately, treatment of hyperlipidemia itself has been substantially facilitated by the introduction of 3-Hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in clinical practice. In the early 1990s, Fuster et al. reported the frequent occurrence of acute coronary events such as unstable angina and acute myocardial infarction with no significant stenosis detected on angiography, and proposed possible involvement of rupture of unstable plaque [1]. Currently, acute coronary syndrome (ACS), acute coronary events without significant vascular stenosis, is a concept proposed on the basis of the observation that nearly 70% of patients with myocardial infarction exhibited coronary artery stenosis of less than 50%.

The plaque-stabilizing action of statins was previously ascribed to their activity of lowering blood cholesterol level. However, many investigators later observed that statins exhibited a direct action of increasing NO production in cultured cells in the absence of cholesterol, which suggests that statins are capable of exerting a direct action on the blood vessel wall (see this issue). Numerous recent studies have revealed new mechanisms of prevention of coronary heart disease by statins: they not only lowered cholesterol level as previously reported, but also contribute directly to plaque stabilization. To date, the following mechanisms have been reported as direct actions of statins on the blood vessel wall, which are independent of their cholesterol-lowering action: 1) improvement of endothelial dysfunction (increase in NO production ascribable to increased expression of endothelial NO synthase gene and enhanced stability of the enzyme itself); 2) reduction of oxidative stress (suppression of conversion of LDL to oxidized LDL); 3) suppression of inflammatory response (suppression of macrophage proliferation and monocyte adhesion to vascular endothelium); 4) suppression of foam cell formation from smooth muscle cells and macrophages (suppression of accumulation of cholesterol ester in smooth muscle cells and macrophages); 5) suppression of weakening of the fibrous cap (suppression of production of collagen-degrading system components such as MMP-1, MMP-9 and urokinase plasminogen activator; 6) angiogenesis within the plaque; 7) enhancement of anti-thrombogenic activity (suppressed expression of PAI-1 gene), and so on. It is obvious from the actions listed above that statins directly influence all steps of the plaque destabilization process.

Among many statins recently marketed, some act directly onto the blood vessel wall to stabilize plaques already formed (so-called vascular statins). At the same time, reports on pleiotropic activities of statins, including improvement of osteoporosis, have accumulated to suggest an extended role of statins [2], not merely as a hypolipidemic agent but also possibly an anti-arteriosclerotic/anti-aging drug. Now, statin research might open a gateway to exploration of aging mechanisms. Active commitment of investigators to clarification of the enigma of the pathogenesis of arteriosclerosis through statin research is therefore strongly encouraged. As described above, statins have activity of improving the vascular remodeling process both quantitatively and qualitatively, and are considered to be active in suppressing arteriosclerosis in general. Then, what kind of statin is most desirable for plaque stabilization? Firstly, most activities of statins that improve vascular remodeling are independent of their cholesterol-lowering activity. Secondly, statins exhibit a direct local effect on vascular lesions. Considering these facts, a statin easily transferred into the blood and exhibiting a potent local action on vascular lesions might be most desirable in view of remodeling improvement.

It is noteworthy to consider the direct inhibition of VSMC proliferation by statins. This action has been reported for most statins currently available, as shown in Fig. 1. The pharmacologically effective concentration varies among individual statins and mutual comparison is not easy. However, it is clear that the most important point in actual inhibition of plaque formation and vascular restenosis is whether a particular statin is delivered to the blood vessel wall in an amount sufficient for its therapeutic effect. The blood concentration of pravastatin corresponds to only 4/10,000 of the level required for inhibition of VSMC proliferation. In contrast, the concentration of fruvastatin in blood is equivalent to its pharmacological level (Fig. 1). Thus, the direct action of statins on the blood vessel wall, with reference to classification of statins based on difference in action on the blood vessel wall might be possible (hepatic statins vs. vascular statins) [3]. Considering drug-todrug variation in the ratio of actual blood concentration and pharmacologically effective concentration, statins may be roughly classified into two groups: vascular statins acting after transfer to the blood vessel wall and hepatic statins active in the liver (Fig. 2). It will not be long before “tailor-made” cholesterol control or atherosclerosis treatment best suited for the condition of each patient is realized by the introduction of even more new statins that will further extend the therapeutic options. This issue reviews the direct action of statins on the blood vessel wall, with reference to classification of statins based on difference in action on the blood vessel wall.

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/187152208784587881

Publication date: June 1, 2008

More about this publication?
  • Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in the medicinal chemistry and rational drug design for the discovery of new Immunology, Endocrine & Metabolic Agents. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics in Immunology, Endocrine & Metabolic medicinal chemistry.

    Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in Immunology, Endocrine & Metabolic drug discovery.
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