Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 8, Issue 2, 2008

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.

Inflammation plays a critical role in the development of atherosclerosis as well as the acute onset of thrombotic complications such as myocardial infarction, a leading cause of death. Accumulation of macrophages expressing proteolytic and thrombogenic molecules may promote plaque disruption and thrombus formation. Clinical evidence suggests that hypercholesterolemia is a major coronary risk factor, further supported by pre-clinical observations that hypercholesterolemia induces oxidative stress in the arterial wall, promoting endothelial cell activation and leukocyte invasion. Recent advances in clinical and preclinical vascular medicine have established that lipid-lowering therapy prevents acute coronary complications by limiting inflammation in atheromata. Dyslipidemia and macrophage activation also promote other forms of cardiovascular problems such as metabolic syndrome and calcification. Further understanding of the mechanism for vascular inflammation will provide new insight into atherogenesis as well as preventive cardiovascular medicine. New approaches, including molecular imaging, may identify subclinical inflamed cardiovascular lesions and monitor effects of therapies such as lipid lowering. (154 words)

Lipid-lowering agents, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiovascular events. However, evidence from recent clinical trials suggests that the beneficial effects of statins may be derived from both lipid lowering and non-lipid lowering, or “pleiotropic” effects. Animal studies suggest that some of these pleiotropic effects of statins are mediated by inhibition of Rho kinase (ROCK). ROCK has been shown important in regulation of vascular tone, cell proliferation, inflammation and oxidative stress. In the cardiovascular system, RhoA/ROCK pathway has also been implicated in angiogenesis, atherosclerosis, cerebral and coronary vasospasm, cerebral ischemia, hypertension, myocardial hypertrophy, and neointima formation after vascular injury. Indeed, in clinical studies, elevated ROCK activity is associated with cardiovascular risks and inhibition of ROCK leads to improved endothelial function. Therefore, modulation of the RhoA/ROCK pathway by statins may provide additional benefits beyond their lipid lowering effects, especially among high-risk cardiovascular patients.

Vascular smooth muscle cell (SMC) migration and proliferation contribute to the pathobiology of atherosclerosis and of instent restenosis, transplant vasculopathy and vein by-pass graft failure. Since mevalonate (MVA) and other intermediates of cholesterol biosynthesis (isoprenoids) are necessary for cell migration and proliferation, inhibition of 3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase, the rate limiting step of the MVA pathway, has the potential to result in antiatherosclerotic effects. Indeed statins, competitive inhibitors of the HMG-CoA reductase, have shown the capability to interfere with migration and proliferation of SMC in diverse experimental models. Here we summarize in vitro, in vivo, and ex vivo evidence of the inhibitory effects of statins on SMC proliferation and migration and discuss the molecular mechanisms involved in their pharmacodynamic action. Altogether, this evidence suggests direct vascular antiatherosclerotic properties of statins. However, it is important to mention that statins failed to prevent intimal thickening when studied in clinical setting characterized by accelerated vascular SMC proliferation and migration (e.g. restenosis after PTCA and instent restenosis), thus leaving open the question of the clinical relevance of these direct vascular effects of statins.

Despite the development of effective immunosuppressive therapy, transplant graft arterial disease (GAD) remains the major limitation to long-term graft survival. Multiple immune and nonimmune risk factors contribute to this vasculopathic disease process; the interplay between host inflammatory cells and donor endothelial cells results in an intimal hyperplastic lesion, whereas alloantigenindependent factors such as prolonged ischemia, surgical manipulation, ischemia-reperfusion injury, and hyperlipidemia may enhance antigen- dependent events, leading to ischemia and graft failure. Several studies suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, exert cholesterol-independent immunosuppressive effects beyond their original lipidlowering effects. Clinical studies demonstrate that statins reduce GAD in human cardiac allografts, improving chances for survival, although it remains unclear whether this is secondary to cholesterol-lowering or other mechanisms. Further studies will provide a firm rationale for using statins in organ transplantation.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are widely prescribed to lower cholesterol levels. Large clinical trials have demonstrated that statins reduce mortality and incidence of cardiovascular events. Although improvement of dyslipidemia is supposed to account for reduction of cardiovascular events by statin therapy, recent reports demonstrated that statins have lipid-independent benefits, so-called “pleiotropic effects”, including improvement of endothelial function, inhibition of inflammation, and augmentation of angiogenic response in ischemic tissues. Statins enhance re-endothelialization of injured arteries and inhibit atherosclerotic lesion development. Here, we overview the favorable effects of statins on endothelial cells and their progenitors and discuss clinical relevance of the vascular effects of statins in re-endothelialization and angiogenesis.

Coronary spasm is involved in the pathogenesis of angina pectoris, acute myocardial infarction and sudden death. It has been revealed that endothelial function was reduced in patients with coronary spasm. Nitric oxide is a key molecule in the pathogenesis of coronary spasm; and the T-786→C polymorphism of the eNOS gene is strongly associated with coronary spasm. However, its precise mechanism(s) remains largely unknown. Also, a therapeutic strategy of coronary spasm has not been well established. HMG-CoA reductase inhibitors (statins) increase endothelial nitric oxide (NO) production, although the precise mechanism of this statin induced increase in NO production remains to be elucidated. We examined endothelial nitric oxide synthase (eNOS) mRNA levels, mRNA stability and the transcriptional activities of the eNOS gene in human umbilical vein endothelial cells treated with fluvastatin and simvastatin. We further examined whether the effects of these statins differ dependent upon the T -786→C polymorphism in the eNOS gene, and whether these statins affect gene expression of replication protein A1 (RPA1), which is known to reduce the transcriptional activity of the eNOS gene with the -786C allele. Utilizing the real-time reverse transcription-polymerase chain reaction, fluvastatin significantly increased eNOS mRNA levels and mRNA stability, and decreased RPA1 mRNA levels. As a result, fluvastatin increased eNOS mRNA levels by enhancing both the transcriptional activity and mRNA stability. The effect of fluvastatin on the transcriptional activity was augmented in the -786C/C genotype, probably because of a decrease in RPA1 gene expression. Simvastatin increased eNOS mRNA levels only by enhancing mRNA stability. The present study suggests that fluvastatin increases endothelial NO activity and thus may be more beneficial to patients with the -786C allele.

Endothelium-derived nitric oxide (eNO) is a central regulator of vascular function and blood flow. eNO is a potent vasodilator, inhibits platelet aggregation and prevents monocytes adhesion. In addition, NO availability is an important determinant of the functional capacity of endothelial progenitor cells and neovascularization. Consequently, eNO plays a central protective role during the pathogenesis of ischaemic stroke. Experimental and clinical studies have demonstrated that statins increase the bio- availability of endothelial NO indirectly via cholesterol-lowering as well as through direct cholesterol-independent mechanisms. On the basis of animal studies and clinical trials, statins have emerged as a potential novel strategy to protect from ischaemic strokes. These data raise the questions whether patients with acute cerebral ischaemia may benefit from intravenous treatment with a statin and, whether these patients are at risk when their ongoing statin treatment is withdrawn.

A number of clinical studies suggest that 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins reduce the incidence of myocardial infarction and other cardio-cerebrovascular events. Recently, the pleiotropic effects of statins have been reported in cardiovascular cells and provided a new insight into the molecular mechanism of cardiovascular and other diseases. The favorable effects of statins could be expanded to antioxidant effects. Statins can block the isoprenylation and activation of members of the Rho family, such as RhoA and Rac1. Rac1 also regulates NADPH oxidase, which is a major source of reactive oxygen species (ROS) in cardiovascular cells. Thus, statins may attenuate oxidative stress through inhibition of Rac1. Interestingly, fluvastatin showed additional hydroxyl radical scavenging activity as potent as that of well known antioxidants, dimethylthiourea and alpha-tocopherol. This antioxidant effect may be derived from the unique chemical structure of fluvastatin. Cardiac hypertrophy is an initial physiological adaptive response of the heart to pressure overload. However, if pressure overload persists, frequently, the heart decompensates and develops “pathophysiological” hypertrophy. Growing evidence suggests that ROS may be involved in the process of cardiac hypertrophy, and recent research has shown that statins can attenuate cardiac hypertrophy through inhibition of Rac1. The new evidence of therapeutic implications of statin therapy as antioxidant therapy will likely yield important new insights.

Statins have been shown to have beneficial effects on myocardial infarction, revascularization, stroke, and cardiovascular mortality in numerous clinical trials. Seven kinds of statins are available today and have different characteristics in their efficacy of LDLlowering, their metabolism and their adverse effects including hepatic injury, muscle disease, renal injury and neurologic injury. Muscle disease is the most discussed adverse effect with the use of statins including rhabdomyolysis, the most serious one. Hepatic injury with high dose statin use should be mentioned, although the incidence is low. Statins are well-tolerated and have been extremely well studied all over the world. As the contribution of statins in preventing cardiovascular events has already been proven, physicians should not hesitate to prescribe statins to patients not only with hypercholesterolemia, but also to those with high risks.

Coronary heart disease (CHD) has been one of the leading causes of death in United States, Japan and EU countries. A large bodies of clinical evidence suggests a causative role for elevated cholesterol in atherosclerosis, and supports treatment of hyperlipidemia [1-3]. Nonetheless, fewer than 50% of Americans who are eligible for cholesterol lowering therapy do actually receive it [4, 5]. Moreover, only about one-third of those treated with hyperlipidemia achieve their target LDL-C goal [5]. Tremendous efforts have been taken to the management of hyperlipidemia. The National Cholesterol Education Program (NCEP) Expert Panel in US [6-8] or Japan Atherosclerosis society in Japan [9, 10] has historically provided consensus recommendations on the evaluation and treatment of hyperlipidemia. The trend of recent recommendations continues toward a more aggressive management of patients with elevated cholesterol levels, particularly if they fall in the high-risk category. The purpose of this article is to provide an overview of current concept of controling dyslipidemia especially with new category of cholesterol absorption inhibitor, ezetimibe in addition to HMG CoA reductase inhibitor or statin.

Statins contribute to stabilization of atherosclerotic plaques not only by reduction in circulating levels of atherogenic lipoproteins, but also by pleiotropic effects such as resolution of plaque inflammation. 18F-fluorodeoxyglucose (FDG) imaging, which is commonly employed for the detection of malignant tumors, has been recently shown to identify inflamed atherosclerotic lesions, and prospective studies have demonstrated close relationship between FDG uptake and the extent of vascular inflammation. The FDG uptake is highly reproducible. Use of statins abrogates FDG uptake, suggesting favorable effect on plaque inflammation. Recent demonstration of FDG uptake in coronary vessels suggests that detection of vulnerable plaques may become a possibility.

Ezetimibe is a cholesterol absorption inhibitors that blocks the intestinal absorption of cholesterol and biliary cholesterol without affecting the uptake of triglyceride or fat-soluble vitamins. The co-administration of ezetimibe with statin has been shown to produce significant incremental reduction in LDL-C beyond that achieved with statin therapy alone. The efficacy and safety of this strategy has been studied in a several trials in a great number of patients. The mean difference between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for total cholesterol (p < 0.0001), LDL-C (p < 0.0001) and HDL-C (p < 0.0001). The probability of reaching the LDL-C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/ statin (p < 0.0001). Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments. Ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL-C goal on statin therapy alone, allowing more patients to reach their LDL-C goal with no increment in the side-effects.