Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 12, Issue 2, 2014

Cardiovascular disease is the leading cause of death worldwide. Recently emerging evidence suggests that cardiomyocyte apoptosis is one of the major pathogenic factors in heart diseases leading to heart failure. Cardiomyocytes undergo apoptosis in response to a wide variety of cellular stresses including protein folding stress at Endoplasmic reticulum (ER). Stressed myocytes elicit an adaptive response referred as Unfolded Protein Response (UPR) by inducing accumulation of heat shock proteins (HSPs) to mitigate the ER stress. HSPs act as molecular chaperons by assisting correct folding of the aggregated misfolded proteins in ER lumen. α-Crystallin B (CRYAB) is an abundant small HSP that confers protection to cardiomyocytes against various stress stimuli. Recent evidence indicates that CRYAB directly interacts with several components of ER stress and also mitochondrial apoptotic pathway. Based on currently available literature this mini review will focus on how CRYAB confers protection to stressed myocardium thereby emphasizing its function as antiapoptotic molecule. Understanding the interplay between CRYAB and the key components in the apoptotic signaling cascade mediated by ER and mitochondria will help in development of novel therapies for cardiac diseases.

Coronary heart disease is the leading cause of mortality worldwide, affecting millions of men and women every year. Elucidation of key signaling factors and their pathways are critical for understanding and developing novel therapeutic targets for protection of the myocardium from ischemia. EGR-1, an immediate early gene and a zinc finger transcription factor plays critical role in various cardiovascular patho-biological processes. This article reviews the growing evidence implicating EGR-1 pathway in myocardial ischemia/reperfusion, cardiac hypertrophy and other cardiovascular complications like atherosclerosis.

Myocardial infarction (MI) is an insidious disease, gently spreading in developed and developing countries. MI is the consequence of hypoxia in myocardial tissue, which may lead to apoptosis, narcosis and followed by cardiac cell death. Activation of apoptotic pathways during MI is frequently reported in clinical, preclinical and post-mortem studies. Several mediators of apoptosis signalling cascades culminate into MI leading to cardiomyocytes death. Such involvements of ischemia-induced apoptosis in MI are widely accepted. Apoptosis is a natural phenomenon for regulating the homeostasis in cellular organelles. Unlike the necrosis, it is a synchronized energy dependent process which is carried out by shrinkage of the cell. This contraction of cells leads to squeezing of nuclei and nuclear chromatin into brusquely demarcated masses. However, such programmed cell death in several tissues, including the myocardium becomes pathogenic under certain conditions. Moreover, reactive oxygen species (ROS) generated oxidative stress also plays a key role in production of apoptosis and several associated signalling alterations which ultimately lead to MI. Recently, certain natural products, especially from the plant kingdom have been evaluated for their anti-apoptotic potential. There is an uprise in the investigations delineating the exact mechanisms through which natural phytochemicals target apoptosis associated MI. This review explores novel signalling pathways and target sites for anti-apoptotic phytochemicals having potential to check the cellular apoptosis consequent to MI. A new vista may explore the prospective treatment of MI by using apoptosis-modulating natural products.

Thrombolytic agents play a major role in the treatment of cardiovascular diseases. Streptokinase is the prominently commercialized thrombolytic drug used for the treatment of cardiovascular diseases. The later studies on staphylokinase (SaK) showed promising results as an alternative fibrinolytic drug. The present study explores the isolation, production and purification of SaK producing Staphylococcus sp. from milk samples. The potent isolate MSA4 of Staphylococcus sp. was selected for production and purification of SaK. The total activity and specific activity of purified staphylokinase was found to be 1266 IU mL-1 and 815.5 IU mg-1, respectively. The partially purified enzyme was lysed the euglobulin clot completely within 18 h of incubation and the purified enzyme showed 79% of blood clot lysis activity.

Fibrinolysis is the ultimate outcome of a cascade of enzymatic reactions in which serine proteases such as plasmin, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) are the key players. Plasmin degrades fibrin into soluble fibrin degradation products. The tPA-mediated plasminogen activation is mainly involved in the dissolution of fibrin in the circulating blood whereas the uPA binds to a specific cellular receptor, resulting in an enhanced activation of cell membrane bound plasminogen. These proteases are regulated by serine protease inhibitors (serpins). Serpin-mediated regulation may occur either at the level of plasmin, mainly by α2-antiplasmin (α2-AP) or at the level of the PAs, mainly by plasminogen activator inhibitor -1 (PAI-1). Other serpins may also be involved including plasminogen activator inhibitor -2 and -3 (PAI-2 and PAI-3), protease nexin-1 (PN-1), C1-inhibitor (C1-INH), placental thrombin inhibitor (PTI), neuroserpin, and yukopin. The serpin-protease reactions serve as potential platforms to develop therapeutics for the treatment and prevention of cardiovascular diseases such as thrombosis and hemorrhage. This review will describe key serpins involved in the regulation of fibrinolytic system, particularly α2-AP and PAI-1, with the focus on their biochemical and biophysical aspects, the pathologies related to their dysfunction or deficiency, their therapeutic roles, and their reported cofactors or modulators.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduces body weight without inducing hyperglycemia. In addition, coagonists have demonstrated lipid lowering property, which was independent of their anorectic effect. Similarly, GLP-1 modulates cardiovascular function which is favorable for treatment of myocardial injury, cardiac dysfunction, cardiac arrhythmias, endothelial dysfunction, and blood pressure, while glucagon has a positive impact on heart rate, cardiac output, ventricular contraction and enhances cardiac performance in animals and humans. Hence, researchers focused on combining these attributes of GLP-1 and glucagon in a single molecule, which was termed as a coagonist. Oxyntomodulin is the naturally occurring coagonist of GLP-1 and glucagon. This review focusses on the coagonists under clinical development discussing activities affecting cardiovascular functions, lipid modulation, direct effect on cardiac functions or other related functions. A comparative analysis of the in vitro and in vivo properties of GLP-1, glucagon and the coagonists is also carried out. This review discusses potential of GLP-1 and glucagon coagonists in treatment of cardiovascular and hemodynamic diseases with attention to GLP-1 or glucagon receptor specific properties as well as the interaction between other therapies.