Abstracts


[Back to top]
Resveratrol: A Therapeutic Promise for Cardiovascular Diseases
Samarjit Das and Dipak K. Das

The heart is an aerobic organ, and most of the energy required for the contraction and maintenance of ion gradients comes from oxidative phosphorylation. Oxidative stress caused by free radicals plays a crucial role in the pathophysiology associated with atherosclerosis, neoplasia and neurodegenerative diseases. Therefore, a great deal of attention has focused on the naturally occurring antioxidant phytochemicals as potential therapy for cardiovascular diseases. One of the most recognized and widely studied compounds is resveratrol, a member of a family of polyphenols called viniferins. Although resveratrol was first isolated in 1940 from the roots of white hellebore (Veratrum grandiflorum), the importance of resveratrol was recognized only after the widely publicized historic "French Paradox" associated with drinking of red wine. Both epidemiological and experimental studies have revealed that drinking wine, particularly red wine, in moderation protects cardiovascular health; however, the experimental basis for such an action is not fully understood. A growing body of evidence supports the role of resveratrol as evidence based cardiovascular medicine. Resveratrol protects the cardiovascular system by multidimensional way. The most important point about resveratrol is that at a very low concentration, it inhibits apoptotic cell death, thereby providing protection from various diseases including myocardial ischemic reperfusion injury, atherosclerosis and ventricular arrhythmias. Both in acute and in chronic models, resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the state-of-the-art technique of cardioprotection), rather than direct effect as found in conventional medicine. The same resveratrol when used in higher doses, it facilitates apoptotic cell death, and behaves as a chemo-preventive alternative. Resveratrol likely fulfills the definition of a pharmacological preconditioning compound and gives hope for the therapeutic promise of alternative medicine. The purpose of this review is to provide evidence in favor of resveratrol to be used as a preventive medicine and related patents for the maintenance of healthy heart.

[Back to top]
Edaravone (3-Methyl-1-Phenyl-2-Pyrazolin-5-one), A Novel Free Radical Scavenger, for Treatment of Cardiovascular Diseases
Yukihito Higashi, Daisuke Jitsuikia, Kazuaki Chayamab and Masao Yoshizumia

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a strong novel free radical scavenger, is used for treatment of patients with acute brain infarction. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Antioxidant actions of edaravone include enhancement of prostacyclin production, inhibition of lipoxygenase metabolism of arachidonic acid by trapping hydroxyl radicals, inhibition of alloxan-induced lipid peroxidation, and quenching of active oxygen, leading to protection of various cells, such as endothelial cells, against damage by reactive oxygen species (ROS). Recently, we have shown that edaravone improves endothelial function through a decrease in ROS in smokers. From a clinical perspective, it is important to select an appropriate drug that is effective in improving endothelial function in patients with cardiovascular diseases. The novel free radical scavenger edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, chronic heart failure, diabetes mellitus, or hypertension. This review focuses on clinical findings and on putative mechanisms underlying the beneficial effects of the antioxidative agent edaravone on the artherosclerotic process in patients with cardiovascular diseases.

[Back to top]
Methylglyoxal and advanced glycation endproducts: New therapeutic horizons?
Kaushik Desai and Lingyun Wu

Advanced glycation endproducts (AGEs) are unavoidable byproducts of various metabolic pathways. They are formed by reactive metabolic intermediates such as methylglyoxal (MG), glyoxal, and 3-deoxyglucosone. These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, which leads to different diseases such as vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, and aging. In recent years, more compounds that prevent the formation of AGEs or degrade the existing AGEs have been produced and patented. They include: 1) aminoguanidine, 2) drugs used in the treatment of type 2 diabetes such as metformin and pioglitazone (patented), 3) angiotensin receptor blockers and angiotensin converting enzyme inhibitors, 4) pentoxyfylline (patented), 5) metal ion chelators desferoxamine and penicillamine, 6) antioxidants such as vitamin C or E, 7) amino group capping agents such as aspirin, 8) enzymes that cause deglycation of Amadori products, the Amadoriases, 9) compounds that mostly break α-dicarbonyl cross-links such as phenacylthiazolium bromide and its stable derivative ALT-711 (Alagebrium), and 10) derivatives of aryl ureido and aryl carboxaminido phenoxy isobutyric acids (patented). While some of these anti-AGE compounds are being used in clinical practice (such as metformin, pioglitazone, pentoxyfylline and aspirin) or tested in clinical trials (such as aminoguanidine and ALT-711), most of them are commonly used as experimental tools to investigate the role of AGEs in different disease conditions.

[Back to top]
The Vascular Endothelin System in Hypertension-Recent Patents and Discoveries
Meri M. Hynynen and Raouf A. Khalil

The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ETA and ETB2 receptors in vascular smooth muscle, and stimulate [Ca2+]i, protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ETB1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ETB1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

[Back to top]
The Role of Angiotensin Type 1 Receptor in Inflammation and Endothelial Dysfunction
Skultetyova Dana, Filipova Slavomira, Riecansky Igor and Skultety Jan

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction.Ang II with AT 1 receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT1 receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT1 receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT1 receptor enhances the activation of nuclear factor NF-κB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT1 receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT1 receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.

[Back to top]
Novel molecular targets in the treatment of cardiac hypertrophy
Mark Luedde, Hugo A. Katus and Norbert Frey

Left ventricular hypertrophy represents the heart's response to increased biomechanical stress such as arterial hypertension or valvular heart disease. Cardiac hypertrophy has traditionally been considered a compensatory mechanism required to normalize wall tension and to maintain cardiac output. However, recent clinical studies as well as several animal models have shown that sustained cardiac hypertrophy is rather a maladaptive process, ultimately leading to heart failure and sudden death independent of the underlying cause of hypertrophy. Throughout the past decade, much effort has thus been spent on deciphering the molecular signaling pathways mediating cardiac growth. Identification of novel molecules regulating cardiac hypertrophy could offer the basis for a new generation of cardiovascular drugs. In this review we focus on recent insights into hypertrophic signaling and consider current and emerging approaches to inhibit hypertrophy with the ultimate goal to prevent or delay the onset of heart failure and sudden death in patients.

[Back to top]
A Review of Sirt1 and Sirt1 Modulators in Cardiovascular and Metabolic Diseases
Pillarisetti Sivaram

Sirt1 (member of the sirtuin family) is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase that removes acetyl groups from various proteins. A wide variety of proteins are Sirt1 substrates; the list includes many transcription factors and cofactors. Deacetylation of these factors may lead to activation or inactivation of the factor, thus impacting downstream gene expression. In addition to direct deacetylation, Sirt1 can modulate protein activity by other mechanisms. Although initial research focused on sirtuin's role in life span extension especially in lower organisms more recent studies show that Sirt1 activity can impact a wide array of proteins implicated in cardiovascular (CV) and metabolic diseases. Several patents have been published in the last 5 years describing the application of sirtuin compounds in the treatment of metabolic diseases. This review will focus on those Sirt1-modifiable proteins that have an impact on CV and metabolic diseases. Pharmacological agents that activate Sirt1 and thus impact the disease process will also be reviewed.

[Back to top]
Oxidative stress in cardiovascular disease: a new avenue toward future therapeutic approaches
Colussi, G. Luca, Catena Cristiana, Baroselli Sara, Nadalini Elisa, Lapenna Roberta, Chiuch Alessandra and Sechi L.A.

ω-3 and ω-6 Polyunsaturated fatty acids (PUFA) are the major families of PUFA that can be found as components of the human diet. After ingestion, both ω-3 and ω-6 PUFA are distributed to every cell in the body where they are involved in a myriad of physiological processes, including regulation of cardiovascular, immune, hormonal, metabolic, neuronal, and visual functions. At the cell level, these effects are mediated by changes in membrane phospholipids structure, interference with eicosanoid intracellular signaling, and regulation of gene expression. Two longchain ω-3 PUFAs, the docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid, are found in fatty fish and other marine sources and might be the putative dietary components thought to modify the cardiovascular risk in subjects consuming high amounts of such food. Evidence of an inverse relationship between fatty fish intake and cardiovascular risk has, in fact, emerged in studies performed more than twenty years ago in Eskimos and has been subsequently confirmed in other ethnic groups. The benefits of ω-3 PUFA might relate principally to prevention of coronary heart disease, coronary artery restenosis after angioplasty, and sudden arrhythmic death. In this brief review, we will cover the general biochemical aspects of ω-3 PUFA, summarize the evidence relating these fatty acids with control of cardiovascular risk factors and prevention of cardiovascular events, and overview the most recent and relevant patents that are related to these issues. More specifically, we will deal with the possibility to use PUFA in association with other molecules that can potentiate their antiinflammatory and antiatherogenic effects.

[Back to top]
Oxidative stress in cardiovascular disease: a new avenue toward future therapeutic approaches
Reiko Inagi.

Oxidative stress is a common denominator in many aspects of the pathogenesis of atherosclerosis and cardiovascular diseases. Some drugs, such as vitamin C, vitamin E, and a free radical scavenger, edaravone, are prescribed with oxidative stress as their main target. Furthermore, of the drugs in current clinical use, such as anti-hypertension reagents including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), and antihyperlipidemic reagents like statins, protect various organs, e.g., vessel, brain, heart, and kidney, via anti-oxidative stress effects in addition to their original pharmacological properties. While results of clinical trials of anti-oxidative stress reagents in patients with cardiovascular disease are contradictory to date, this may be explained by a variety of reasons such as an inadequate study design. More competent anti-oxidative reagents are awaited, and superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H oxidase inhibitors, which regulate intracellular redox reaction and subsequently inhibit oxidative stress, are among promising candidates of future drug developments currently receiving much interest. In this review, the current advances will be highlighted in development of novel anti-oxidative therapeutic approaches against cardiovascular diseases.

[Back to top]
Role of PPAR in cardiovascular diseases
Saibal K. Das and Ranjan Chakrabarti

Cardiovascular disease (CVD) is the most critical global health threat, which contributes more than one third of global morbidity. CVD includes heart disease, vascular disease, atherosclerosis, stroke and hypertension. The most important independent risk factors for CVD include dyslipidemia along with hypertension, obesity, sedentary lifestyle, diabetes and chronic inflammation. These factors are directly regulated by diet, metabolism and physical activity. Diets rich in fat and carbohydrate coupled to sedentary lifestyles have contributed to the increase in dyslipidemia, type 2 diabetes, obesity and CVD in the world. Discovery of Peroxisome Proliferator Activated Receptors (PPARs) as a key regulator of metabolic pathways has led to significant insight into the mechanisms regulating these processes. Three PPAR subtypes, encoded by distinct genes, are designated as PPAR-α, PPAR-δ (also know as β) and PPAR-γ. PPARs act as nutritional sensors that regulate a variety of homeostatic functions including metabolism, inflammation and development. PPAR-α is the main metabolic regulator for catabolism whereas PPAR-γ regulates anabolism or storage. PPARs are expressed in the cardiovascular system such as endothelial cells, vascular smooth muscle cells and monocytes /macrophages. It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. In 1997, a Glaxo patent described that Troglitazone (first PPAR-g ligand to reach market) reduced TNF-induced VCAM1 expression in HUVECs indicating the potential benefit in atherosclerosis. A series of patents from Eli Lilly and Dr. Reddy's Laboratories Ltd. between 1999 and 2005 described a variety of PPAR-α and -α,γ dual ligands in a number of patents having glucose, triglyceride, cholesterol lowering, HDL elevating and body weight reducing activity. Patents from Metabolex and Tularik in 2001 and 2002 described the beneficial effects of SPPARM molecules for insulin resistance and diabetes, without showing concern on PPAR-g related side effects such as edema and body weight. GSK and Takeda described the potential effects of PPAR-δ modulators during 2001 to 2004 in few patents.Several clinical and preclinical studies have demonstrated the beneficial effects of PPAR ligands on various cardiovascular risk factors. This review intends to capture some of the key studies in this area as is described in some recent patents and literature.