Current Medicinal Chemistry - Volume 21, Issue 11, 2014

Ranolazine has primarily been developed and so far approved as an antianginal drug. However, it also has potentially interesting and relevant antiarrhythmic properties. Its antiarrhythmic effects are mainly based on the blockade of sodium currents, in particular of the late sodium current. Experimental and clinical studies have revealed an antiarrhythmic effect of ranolazine in atrial fibrillation as chronic or “pill in the pocket” therapy. Of note, this effect was preserved in the setting of chronic heart failure. Furthermore, an antiarrhythmic effect has also been shown in experimental models of ventricular tachyarrhythmias. In addition, prevention of ventricular tachyarrhythmias has been demonstrated in patients with structural heart disease. A few late sodium current inhibitors are evaluated for antiarrhythmic properties in experimental studies. However, randomized clinical data is not yet available for these recently developed agents and larger controlled trials are necessary before recommending ranozaline as a novel antiarrhythmic drug.

Human congestive heart failure is accompanied by structural and electrical alterations leading to the development of an arrhythmogenic substrate. This substrate is associated with the “sudden cardiac death” due to ventricular tachycardia or ventricular fibrillation. Multiple studies link distinct transcription factors to the transcriptional regulation of genes related to the formation of an arrhythmogenic substrate. In addition to cardiac hypertrophy the up- or downregulation of ion channels, calcium-handling proteins, and proteins forming gap junctions play a pivotal role in the progression of heart failure. This review summarizes the transcriptional regulation of selected genes implicated in the formation of an arrhythmogenic substrate. In this context we provide an overview of relevant transcription factors, activating stimuli and pathways, the evidence of binding to respective elements in the promoter of target genes and the associated mRNA regulation in animal models. Finally, possible therapeutic consequences are discussed.

In the recent years, Ca2+/calmodulin-dependent protein kinase II (CaMKII) was suggested to be associated with cardiac hypertrophy and heart failure but also with arrhythmias both in animal models as well as in the human heart. This article focuses on the role of CaMKII for excitation-contraction coupling but more explicitly it highlights major CaMKIIdependent proarrhythmogenic mechanisms including SR Ca2+ leak and late Na+ current. Because a clinical significance of CaMKII is implied for both mechanisms, CaMKII inhibition is suggested to be a therapeutical approach in the near future.

The development of pharmacologic agents for the treatment of diseases is still challenging, especially in rare inherited arrhythmia syndromes like long and short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The underling pathophysiologic mechanism of these inherited diseases is in most cases either a gain- or a loss-of-function due to mutations in ion channel genes. Although the biophysical properties of mutant channel subunits are well studied, little is known about the targeting effect of specific pharmacologic agents. In this review, we focus on the therapeutic (in vivo) and the experimental (in vitro) approaches in the most common inherited forms.

In the face of an aging population and thereby an increasing number of patients suffering from heart rhythm diseases development of therapeutic agents is one of the major challenges in modern biomedical research. Antiarrhythmic drug discovery was mainly hindered by the limited knowledge of the molecular underpinnings of cardiac electrophysiology in health and disease. In recent years, the zebrafish has emerged as an effective model organism to dissect the pathology of human disorders in particular in the area of cardiovascular diseases. Especially, certain aspects of cardiac electrophysiology of the zebrafish such as action potential or heart rate are similar to that of humans. The zebrafish shares many features of human physiology and body plan but it develops extra-uterine and is initially transparent, allowing detailed and comprehensive characterization of cardiac development and function in vivo. Moreover, zebrafish are well amenable to large-scale forward and reverse functional genomics approaches, which has led to the identification of numerous novel genetic key-players and potential targets of cardiac disease. In this context, several zebrafish lines with mutations in defined ion channels have emerged as novel vertebrate models for human arrhythmia disorders such as long or short QT syndrome. In addition, due to its size and the high number of progeny, zebrafish are very suitable for rapid in vivo analysis of the bioactivity of small molecules and their therapeutic potential, especially in the context of cardiovascular diseases such as arrhythmias. In this review we highlight an assortment of established zebrafish models that enable the dissection of human heart rhythm disorders and the potential of this model system for the discovery of novel antiarrhythmic targets and drugs.

In the search for novel antiarrhythmic strategies, the cardiac Na+/Ca2+ exchanger (NCX) seems to be a promising target. Recent insights into the role of NCX in proarrhythmia stem from transgenic murine models with knockout or overexpression of NCX. There are significant differences regarding cellular electrophysiology, excitation-contraction coupling and Ca2+ handling when comparing mice to higher mammal and most importantly human physiology. We here review findings derived from transgenic mouse models regarding the role of NCX in the generation of arrhythmia and discuss principle aspects to consider when translating physiological and pathophysiological mechanisms from mouse models into human physiology and the clinical context.

Dysregulation of receptor tyrosine kinases (RTKs) in cancer cells is extremely common. Overexpression of human epidermal growth factor receptor (EGFR/HER) tyrosine kinase is correlated with tumor aetiology, progression and poor prognosis. Their activation is also observed frequently in human cancers. Therefore, RTKs have been identified as important therapeutic targets in oncology. Many therapeutic methods have been developed based on inhibition of EGFR and HER-2. Herein, we will discuss recent progress in the development of EGFR/HER-2 tyrosine kinase inhibitors. We will focus on the design strategies, pharmacological profiles and structure-activity relationships (SARs) of EGFR and HER-2 inhibitors.

Estrogen aids in neo-vascularization of various tumors during hypoxic conditions, however the role of estrogen within the hypoxic environment of thyroid cancer is not known. In a series of experimentations, using human thyroid cancer cells, we observed that estrogen and hypoxia modulate the hypoxia inducible factor-1 (HIF-1) signaling which is abrogated by the anti-estrogen fulvestrant and the HIF-1 inhibitor YC-1 (3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole). Furthermore, we found that the conditioned medium from estrogen treated thyroid cancer cells lead to enhanced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs) which is abrogated by HIF-1 inhibitor. These findings, in addition to our previous and other scientific literature data, lead us to conclude that estrogen and hypoxia are interlinked in thyroid cancer and can equally modulate epithelial-endothelial cell interactions by mediating key cellular, metabolic and molecular processes of thyroid cancer progression. We believe that the hormonal component and cellular adaptation to oxygen tension of cancer cells are functionally equivalent with a cellular transition that can be exploited clinically for a combinational approach for thyroid cancer treatment involving antiestrogens as well as anti-hypoxic agents.

Apoptotic cell death has been reported in human oocytes and preimplantation embryos under in vivo and in vitro conditions. BCL-2 family proteins comprise both anti- and pro-apoptotic members, which are likely to play a key role in controlling oocyte and early embryo survival. However, very limited data are available on their expression kinetics during human early embryonic development. Using our DNA microarray data, we analyzed the expression pattern of 21 BCL-2 family genes in human mature MII oocytes, day 3 embryos and day 5/6 blastocysts from patients who underwent in vitro fertilization (IVF). Selected genes were further validated by qRT-PCR and their subcellular localization analyzed by immunofluorescence confocal microscopy. Our results suggest a switch from oocyte-inherited BCL-2 family transcripts, such as BCL2L10, to embryo-produced transcripts after embryonic genome activation, including BIK, BCL2L11 and NOXA. Moreover, the pro-apoptotic gene BCL2L13 was constitutively expressed throughout human early embryonic development. Remarkably, day 3 embryos expressed more BCL-2 pro-apoptotic genes than mature MII oocytes and day 5/6 blastocysts, suggesting that embryos at this stage are more prone to apoptosis. This is further supported by an absence of cleaved Caspase-3 in the oocyte and its presence in the embryo. Using a drug that induces apoptosis (gambogic acid), we were able to show activated Caspase-3 in the oocyte in addition to an alteration of BCL2L13 protein localization. Similarly BCL2L13 localization was altered in degenerated oocytes. This study opens new perspectives for understanding the molecular regulation of human oocyte and pre-implantation embryo survival and death.