Current Pharmaceutical Design - Volume 15, Issue 27, 2009

Coronary heart disease is the leading cause of morbidity and mortality worldwide. Atherosclerosis is a common denominator underlying most clinical manifestations of cardiovascular disease. It is a complex inflammatory process characterized by the cross-talk between excessive inflammation and lipid accumulation. Despite of extensive research, there are several unmet needs in the management of atherosclerosis. Dyslipidemia is one of the main risk factors leading to atherosclerosis. Hitherto, treating hyperlipidemia with the use of statins is the main pharmacological intervention for prevention of atherosclerosis-related disorders. Despite significant clinical benefits associated with statin treatment, monotherapy with statins is frequently insufficient since the reduction of the risk for major coronary events is only 30%. Thus, there is a need for new drugs with different mechanisms of action to directly inhibit atherosclerosis. Both the accumulating knowledge of the molecular mechanisms of atherogenesis and new strategies in drug design and synthesis are expected to bring about alternative therapeutic options in the treatment of atherosclerosis-related disorders. Pharmaceutical industry is either improving existing molecules or synthesizing novel molecules against new targets aiming at direct inhibition of atherosclerosis. In addition, several drugs already in use for cardiovascular and metabolic disorders appear to possess direct antiatherosclerotic properties due to mechanisms of action unrelated to their main effects. We have recently published an overview of all different classes of novel molecules targeting dyslipidemia and atherosclerosis [1]. In the present series of articles, some of the most promising developments in atherosclerosis-related research relevant to drug development are thoroughly reviewed, including novel molecules targeting dyslipidemia and atherosclerosis, anti-atherosclerotic potential of established therapeutic agents for other indications, as well as recent developments in knowledge of pathophysiologic pathways related to atherosclerosis.

The accumulation of lipids within arteries remains to be the initial impulse for the pathogenesis of atherosclerosis; however, both inflammation and oxidative stress are considered to play a critical role in this process. Several lipid lowering drugs are used as the first line therapy in atherosclerosis; however, different agents have been found to exhibit beneficial effects which are independent of their lipid lowering activity. Both statins and fibrates have been reported to exert anti-inflammatory and anti-oxidative effects in addition to their anti-atherosclerotic actions. Furthermore, anti-hypertensive, anti-diabetic and anti-platelet drugs, which reduce oxidative stress and inflammation, have been shown to attenuate atherosclerosis. In addition, novel substances such as HDL-related agents, cyclopentenone prostaglandins, lipoprotein-associated phospholipase A2 inhibitors, 5-lipoxygenase pathway inhibitors, acyl CoA: cholesterol acyltransferase inhibitors, analogues of probucol and lysophosphatidic acid antagonists have been developed for the treatment of atherosclerosis as a consequence of their actions on oxidative stress and inflammation. The present article reviews the involvement of inflammation and oxidative stress in the pathogenesis of atherosclerosis and focuses on the mechanisms of some clinically used as well as potential anti-atherosclerotic substances with anti-inflammatory and anti-oxidative properties.

Atherosclerosis is a complex inflammatory process characterized by the cross-talk between excessive inflammation and lipid accumulation. In the past few years, compelling evidence suggests that statins can decrease vascular inflammation and attenuate the development of atherosclerosis through their so-called “pleiotropic effects”. These cholesterol-independent effects are predominantly due to their ability to inhibit isoprenoid synthesis. In particular, inhibition of geranylgeranylpyrophosphate synthesis leads to inhibition of Rho and its downstream target, Rho-kinase (ROCK). Thus, one of the beneficial effects of statin therapy could be due to inhibitory effects on ROCK. ROCK is involved in mediating diverse cellular functions such as smooth muscle contraction, cell migration and proliferation. While increased ROCK activity is associated with endothelial dysfunction, cerebral ischemia, coronary vasospasms and metabolic syndrome, the inhibition of ROCK by statins or selective ROCK inhibitors leads to up-regulation of endothelial nitric oxide synthase (eNOS), decreased vascular inflammation, and reduced atherosclerotic plaque formation. This review will focus on the impact of ROCK in cardiovascular disease and its contributory role to vascular inflammation and the atherosclerosis.

The inflammatory environment within the atherosclerotic lesion stimulates the 5-lipoxygenase pathway of arachidonic acid metabolism, leading to the biosynthesis of the potent lipid inflammatory mediators leukotrienes. The present review summarizes the components of this pathway; the enzymes 5-lipoxygenase (5-LO, ALOX5) with its activating protein, FLAP (ALOX5AP), LTA4 hydrolase and LTC4 synthase, as well as the receptors for leukotriene B4 (BLT1 and BLT2) and cysteinyl-leukotrienes (CysLT1 and CysLT2), respectively. Genetic variations within the genes encoding these proteins have been associated with cardiovascular risk. Inhibiting the 5-lipoxygenase pathway through either leukotriene synthesis inhibitors or leukotriene receptor antagonists in experimental models of atherosclerosis has however generated contradictory results. Several inhibitors of the 5-lipoxygenase pathway are now evaluated in clinical trials of patients with cardiovascular disease.

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) represents an anti-atherosclerotic principle. NO bioavailability is decreased in atherosclerosis due to increased NO inactivation by reactive oxygen species and reduced NO synthesis. Various types of vascular pathophysiology are associated with oxidative stress, with NADPH oxidases as the major source of reactive oxygen species. These inactivate NO. Also, oxidative stress is likely to be the main cause for oxidation of the essential NOS cofactor, tetrahydrobiopterin (BH4). A lack of BH4 leads to eNOS uncoupling (i.e., uncoupling of oxygen reduction from NO synthesis in eNOS). Based on these pathomechanisms, the therapeutic potential of a number of compounds is discussed in this review: (1) NO donors; (2) L-arginine; (3) folic acid; (4) BH4 and its precursor sepiapterin; (5) compounds that upregulate eNOS and concomitantly maintain eNOS activity (e.g. midostaurin, betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds that enhance the de novo synthesis of BH4 by stimulating expression or activity of GTP cyclohydrolase I; and (7) 3-hydroxy-3-methylglutarylcoenzyme A inhibitors (statins) and drugs interrupting the renin-angiotensin-aldosterone system. Statins, angiotensin II type 1 receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, the aldosterone antagonist eplerenone and the renin inhibitor aliskiren enhance NO bioactivity and reduce atherosclerosis progression through multiple mechanisms.

The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis and cardiovascular disease (CVD) in humans. One of the major mechanisms whereby HDL particles protect against atherosclerosis is that of reverse cholesterol transport from atherosclerotic lesion macrophages to the liver. HDL particles also exhibit various antiatherogenic and cardioprotective effects by modulating the function of various cells including the cells of the artery wall and by expressing antioxidant, anti-inflammatory, antithrombotic and antiapoptotic effects. Most these effects are mediated by various lipid and protein HDL components. A plethora of studies have been conducted in order to shed light on the mechanisms by which each HDL component contributes to the functionality of this lipoprotein. The complete elucidation of these mechanisms will significantly contribute to current efforts focused on the development of therapeutic strategies to promote the antiatherogenic potency of HDL. The present review discusses current knowledge on the biological activities of the major apolipoproteins and enzymes associated with HDL, which may significantly contribute to the overall antiatherogenic and cardioprotective effects of this lipoprotein.

Although treatment with statins significantly reduces adverse cardiovascular outcomes, several studies have shown that cardiovascular events continue to occur in two thirds of all patients. A logical pharmacologic approach to further reduce cardiovascular disease mortality should be focused on direct modifiers of atherosclerosis or lipid-modifying agents with different mechanism of action than existing drugs against dyslipidemia. Squalene synthase inhibitors can decrease circulating low-density lipoprotein (LDL)-cholesterol by an increased expression of hepatic LDL receptors in a similar manner to statins. Also, depending on their structure, they may possess antiatherosclerotic properties independent of their lipid-modifying effects. This review, following a brief introduction to different classes of squalene synthase inhibitors and representative molecules, presents the accumulating in vitro and in vivo experimental evidence relevant to squalene synthase inhibitors EP2306 and EP2302 and discusses their properties. EP2306 and EP2302 show a similar inhibitory effect in the progression of atherosclerosis in the cholesterol-fed rabbit. Moreover, EP2306 showed a significant long-term antiatherosclerotic effect not shared by simvastatin or their combination in this animal model. EP2302 also showed a favorable effect in the regression of pre-established atherosclerotic lesions. It is reasonable to hypothesize that EP2302, due to its NO-releasing and enhancing properties, could have additional advantages compared to EP2306. Treatment with EP2300 compounds did not adversely affect liver transaminases or cause toxicity on various organs of the cholesterol-fed rabbit. The satisfactory safety profile of EP2300 compounds in this animal model is a promising finding in view of future clinical studies.

Type 2 diabetes is associated with substantially increased cardiovascular mortality. The need to reduce the progression of atherosclerosis alongside lowering blood glucose levels is now well established. Ideally, pharmaceutical treatment should address both of these needs. This review summarises current evidence of the anti-atherosclerotic effects exerted by oral antidiabetic agents. Metformin has so far consistently succeeded in reducing cardiovascular morbidity and mortality and exerting beneficial effects on lipids. Of the new agents, thiazolidinediones (rosiglitazone and pioglitazone) have been most widely studied. They have a favourable effect on fat distribution and improve lipid profile, fibrinolysis and endothelial function. Moreover, they reduce blood pressure and inflammatory markers, attenuate the progression of carotid intima-media thickness (CIMT) and may reduce the rates of coronary restenosis following percutaneous coronary intervention. Glinides (repaglinide and nateglinide) have also been documented to improve endothelial function and lipid profile, to reduce oxidative stress, platelet activity and inflammatory markers, and to diminish the progression of CIMT. Finally, acarbose may significantly reduce new cases of hypertension and cardiovascular events, as well as diminishing the progression of CIMT in patients with impaired glucose tolerance. Interestingly, some of these beneficial effects appear to be independent of the antidiabetic action. Thus, oral antidiabetic agents are now emerging as useful tools for the attenuation of the atherosclerotic activity and for the protection of the vasculature in patients with type 2 diabetes.

The growing knowledge about genetic influence on cardiovascular diseases (CVD) combined with the recently generated amounts of genomic data hold promise to the identification of new markers for atherosclerotic CVD. Cardiovascular pharmacogenomics and pharmacogenetics have now the potential for leading to identification of genetic contributors and therefore to the development of predictive genetic tests that could optimize drugs efficacy and minimize toxicity. Clinical studies have shown that genetic variations within cytochromes P450 (CYPs), 3-Hydroxyl-3- Methylglutaryl Coenzyme A Reductase (HMGCR) and apolipoprotein E (APOE) genes influence individual's response to lipid lowering statins. Furthermore, development of antagonists or inhibitors of molecules such as peroxisome proliferator-activated receptors (PPARs), lipoprotein-associated phospholipase A2 (Lp-PLA2), angiotensin-converting enzyme (ACE), angiotensin receptors and tumor necrosis factor (TNF)-alpha could be another alternative to prevent atherosclerosis. In addition, novel molecules under the name of biologics including family of peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), urocortin, apelin and antimicrobial peptides (AMPs) could be considered as new targets for the prevention and treatment of CVD. In this article, we will focus mainly on recent genomic advances in the development of new markers and therapeutic agents for CVD. We present an array of molecules that could have pharmacological benefit for the treatment of heart disease. We also discuss in details new strategies including biologics, which are actually the focus of companies for clinical development of therapeutic drugs. All these efforts provide optimism and attractive promise to cure CVD.