Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 6, Issue 1, 2008

One of the main approaches to the treatment of cardiovascular diseases is to block pathways and enzymes within the Renin-Angiotensin System (RAS) involved in the modulation of Angiotensin II. Besides this complex system, many other alternative strategies may represent interesting targets for new and more effective cardiovascular therapies. Many different approaches have led medicinal chemists to develop new molecules with the aim of improving current antihypertensive therapies. The development of these new compounds is based on different strategies which include the synthesis of new hybrid compounds in which two or more pharmacophore groups are combined together to give a new entity with better pharmacodynamic properties and fewer side effects, and the development of new molecules with targets such as renin, angiotensin (1-7) and urotensin-II. The aim of this review is to present various approaches used to improve antihypertensive therapy, developing both original molecules with new mechanisms of action (such as renin inhibitors, or Mas-agonists) and new hybrid cardiovascular drugs targeting multiple factors involved in hypertensive disease (NO-ACE inhibitors, NO-sartans, AT1/ETA antagonists).

Oxidative stress results from an imbalance, an excess of oxidants, depletion of antioxidants or failure to repair oxidative damage induced by reactive oxygen species. A vast amount of evidence implicates oxygen-derived free radicals and high-energy oxidants as mediators in many pathological conditions of inflammation, shock, and organ responses to ischemia/reperfusion, which arise during a number of clinical surgical interventions, including transplant graft rejection and coronary bypass surgery, and in such diseases as, diabetes, atherosclerosis, hypertension, organ ischemia/reperfusion, cardiovascular inflammation, cardiac/brain infarction, cancer, pulmonary emphysema and autoimmune diseases. To eliminate or attenuate oxidative stress, antioxidant therapies have been developed and may be of great help to these patients. This review describes recent developments in the field of oxidative stress research and antioxidant function, summarizes new pharmacological strategies that are ongoing in antioxidant therapy with small molecules, free radicalscavenging enzymes, superoxide dismutases, catalase mimetics, flavonoids, vitamins and poly polymerase inhibitors, and presents experimental and clinical evidence of the role of antioxidants in diseases.

CAWS is a mannoprotein-beta-glucan complex obtained from the culture supernatant of the fungal pathogen Candida albicans. CAWS exhibits various biological activities, and induces prominent vasculitis of the aortic valve and the coronary arteries in mouse. A significant difference was noted in the susceptibility to and the degree of vasculitis induction among mouse lines. The difference in cytokine production among mouse lines may be strongly related to that difference, namely, IL-6, IFN-γ and TNF-α presumably act as positive factors, and IL-10, as a negative regulator. On the other hand, as a structural component of the inducing substance, the presence or absence of β-1,2-mannose residues was suggested to be closely related to the activity. An understanding of the molecular mechanisms underlying this model could lead to the conquest of many modern diseases. This model is also expected to be useful for the development of new therapeutic drugs for vasculitis and cardiovascular diseases.

The adult mammalian heart, including humans, harbors bone fide cardiac stem cells (CSCs) distributed throughout the atria and ventricles. Their discovery almost four years ago initiated a brand new field of cardiac regenerative biology that has profoundly changed the outlook of developmental and adult cardiac biology/physiology and the potential for treating cardiac failure. Indeed, despite its initial hesitance, the research community has now accepted that the heart has an endogenous myocardial regenerative potential owed to CSCs, which challenges the previous accepted notion of the adult heart as a post-mitotic organ. Also, burgeoning evidence is converging to the possibility that CSCs are actually the founder of the heart in the embryonic life. CSCs are involved in cardiac cellular homeostasis during aging and adaptation to physiological and pathological stress. When transplanted into damaged hearts, CSCs have the capacity to generate significant new myocardial tissue and ameliorate ventricular function. However, more relevant for translational research and its application for future regeneration protocols, this reservoir of CSCs can also be activated by local injections of several growth factors or through the administration of systemic drugs, such as statins, to obtain beneficial results similar to those of CSC transplantation. The present review highlights current knowledge on the biology of CSCs and the prospects of CSC activation in situ, without the need for cell expansion in vitro and consequent transplantation.

Stem cells hold considerable promise for cardiovascular rescue in patients with heart failure due to myocardial infarction or hereditary cardiomyopathies. However, cardiogenesis, one of the earliest and most complex morphogenetic events in the embryo, is only partially exploited at molecular level. The yield of myocardial cells spontaneously derived from human embryonic or adult stem cells is extremely low (usually less than 0.1%). Moreover, it is now evident that secretion of specific growth factors from transplanted stem cells may activate angiogenic, antiapoptotic and antifibrotic paracrine patterning within the recipient heart, playing a major role in tissue repair. Within this context, targeting stem cell fate at the level of gene expression represents a potentially powerful therapeutic approach to afford a high-throughput of cardiovascular lineage commitment and paracrine secretion of “trophic factors”. Cell-based phenotypic- and pathwayspecific screens of natural and synthetic compounds have provided a number of molecules achieving selective control of stem cell growth and differentiation. Novel hyaluronan mixed esters of butyric and retinoic acids have been recently synthesized, emerging as new tools for manipulation of cardio/vasculogenic gene expression through the modulation of targeted signaling pathways and chromatin-remodeling enzymes. These molecules have coaxed both murine embryonic and human mesenchymal stem cells towards cardiovascular decision and paracrine secretion of bioactive factors, remarkably enhancing the rescuing potential of human stem cells in in vivo animal models of myocardial infarction. These molecules may ultimately provide new insights in stem cell biology and pave the way to novel approaches in tissue engineering and cardiovascular repair.

Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins, and an important antiinflammation drug target. Recent focus has been placed on the role of COX-2 in heart function and pathology, due to the finding that specific COX-2 inhibitors significantly increased the risk of heart disease in chronic users. However, the exact role of COX-2 in cardiac physiology and disease remains controversial due to the conflicting data reported. Roughly equal numbers of reports have shown either a detrimental role or a protective role for COX-2 in heart in experimental models. Here we attempt to provide a background on the more general roles of COX-2 in pathophysiology, as well as molecular mechanisms employed to control COX-2 expression. This background provides a basis for better understanding the functional role of COX-2 in human heart pathologies, based on the results of COX-2 pharmacological inhibitor studies in humans as well as COX-2 expression in human heart disease. Furthermore, we will explore the experimental evidence implicating different intracellular molecular signaling cascades that regulate COX-2 expression in cardiomyocytes. All of this data permits a more mechanistic understanding of the published studies using pharmacological inhibitors of COX-2 in experimental models of heart pathology. Lastly, we will examine the use of genetic manipulation of COX-2 in mice as one of the future avenues in an attempt to resolve the role of COX-2 in cardiac physiology and pathology.