Current Drug Targets - Volume 18, Issue 15, 2017

Background: Early reperfusion of the blocked vessel is critical to restore the blood flow to the ischemic myocardium to salvage myocardial tissue and improve clinical outcome. This reperfusion strategy after a period of ischemia, however, may elicit further myocardial damage named myocardial reperfusion injury. The manifestations of reperfusion injury include arrhythmias, myocardial stunning and micro-vascular dysfunction, in addition to significant cardiomyocyte death. It is suggested that an overproduction of reactive oxygen species, intracellular calcium overload and inflammatory cell infiltration are the most important features of myocardial ischemia-reperfusion injury. Objective: In this review, various pharmacological interventions to treat myocardial reperfusion injury including the antioxidant flavonols, hydrogen sulfide, adenosine, opioids, incretin-based therapies and cyclosporin A which targets the mitochondrial permeability transition pore are discussed. Conclusion: The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic.

Background: Experimental studies of acute myocardial infarction have revealed that up to half of the final infarct size may be due to reperfusion injury rather than the initial ischemic incident. Research over the past three decades has deepened our understanding of the molecular mechanisms underlying ischemic reperfusion injury and several therapeutic strategies to decrease the incidence and severity of reperfusion injury have been explored. Objective: To discuss the promising therapies and future perspectives on methods to attenuate myocardial reperfusion injury. Results: Existing therapies that address reperfusion can be divided into two major groups comprising nonpharmacological and pharmacological interventions. Myriad pharmacological and nonpharmacological approaches to reduce lethal reperfusion injury have been employed. Although many initial clinical studies were negative, more recent proof-of-concept clinical trials are promising. To date, the most encouraging results are with ischemic postconditioning, remote ischemic preconditioning, ANP, adenosine, cyclosporine and exenatide. Conclusion: Studies demonstrate that nonpharmacological and pharmacological conditioning can be used together as part of a multifaceted approach to improve clinical outcomes in patients with ischemic heart disease.

Background: Due to their exceptional stability in the circulation, microRNAs (miRs) are being identified as promising biomarkers. On the other hand, their propensity to regulate networks of functionally closely related genes and relative ease of delivery makes them attractive targets for therapy. However, neither application is without challenges, especially as it applies to ischemic coronary artery disease (CAD). Objective: This review will: 1) describe miRs which have been most consistently found to be associated with the most common manifestations of CAD, including atherosclerosis, angina pectoris, myocardial infarction and myocardial reperfusion through arteriogenesis, 2) emphasize those miRs which are also altered in metabolic syndrome and its component pathologies, 3) discuss challenges which currently prevent clinical application related to inconsistencies between findings in cell culture, animal models and among human studies, as well as technical challenges, and 4) offer some suggestions towards resolutions of these discrepancies. Conclusion: While miRs can be used as reliable biomarkers for myocardial infarction, their use as biomarkers for other forms of ischemic CAD, as well as therapy for CAD await further investigation.

Background: Cardiovascular disease is still the most frequent cause of death in both developed and developing countries while metabolic syndrome and myocardial ischemia reperfusion (I/R) injury are the common risk factors responsible for the impaired cardiac function. Transient receptor potential (TRP) channels are non-selective cation channels, that sense a broad range of stimuli from physical conditions such as stretch, to chemicals including capsaicin. Objective: The diverse studies have revealed multifunctional roles of TRP channels in the physiological conditions and various diseases while some members of TRP channel superfamily are demonstrated to participate in the pathophysiology of cardiometabolic diseases and myocardial ischemia reperfusion injury. Here we discuss the roles of TRP channels in myocardial ischemia reperfusion and cardiometabolic diseases and their potential use in treating these diseases. Results: Regulation of TRP channels facilitates the control of metabolic syndrome such as obesity, diabetes mellitus, hypertension, and atherosclerosis. This review presents an overview of our current knowledge regarding the physiological functions of TRP channels in the metabolic and cardiovascular systems and their contributions to cardiometabolic diseases and I/R injury. Conclusion: On the basis of these discoveries, the therapeutic potential of targeting novel TRP channels can be proposed for the treatment of cardiometabolic diseases and I/R injury.

Background: Cardiovascular diseases, especially ischemic heart disease and cardiometabolic disease, remain to be the leading cause of morbidity and mortality worldwide. Despite recent progress in diagnostic and therapeutic approaches, the incidence of cardiovascular disease is still rising. Therefore, alternative favorable treatment is urgently needed to rescue the fast growing numbers of patients. Objective: Herein we aimed to review the relevant role and explore the possibility of SIRT1 as a promising target for protection of heart from ischemia/reperfusion injury and cardiometabolic diseases. Results: The activation of SIRT1 participates in a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance in heart ischemia injury and cardiometabolic disease. Conclusion: Current medication targeting SIRT1 may represent a new therapeutic trend for the prevention of cardiovascular disease that is related to energy balance and metabolism.

Background: The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases. Objective: The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke. Results: IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners. Conclusion: IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders.

Background: Cardio-cerebral-vascular diseases, including myocardial infarction, atherosclerosis, hypertension, and stroke etc, are the major reasons for morbidity and mortality all over the world. Recent studies showed that inflammation exerts an important impact on the pathogenesis and development of cardio-cerebral-vascular diseases. “The cholinergic anti-inflammatory pathway”, mainly modulated through α7 nicotinic acetylcholine receptor (α7nAChR), has attracted much attention. Objective: The purpose of this review was to discuss the role of α7nAChR during the pathological processes in myocardial infarction, atherosclerosis, hypertension and stroke. Results: Most of the existing literatures involved in studying on myocardial infarction, atherosclerosis, hypertension and stroke showed that activation of α7nAChR might be a potential strategy for the prevention and treatment of these diseases. Conclusion: Targeting α7nAChR to combat inflammation might be a novel therapy in cardiocerebral- vascular diseases.

Background: Global burden of cardiometabolic disease warrants development of newer treatment strategies. Apelin is ubiquitously expressed endogenous peptide which is a ligand for the apelinergic (APJ) receptor. Apelin/APJ receptors regulate a variety of biological functions and have been implicated in cardiovascular and metabolic homeostasis. Consequently, the apelinergic pathway represents an attractive target to treat conditions associated with cardiometabolic syndrome. Objective: This review highlights the important regulatory role played by apelin in energy metabolism and cardiovascular function, and potential avenues that could be harnessed for therapeutic benefit. Conclusion: Apelin/APJ system is a druggable target to treat or prevent a variety of cardiometabolic diseases.

Background: Diabetes mellitus (DM) caused 1.3 million deaths in 2010, and cardiovascular disease is the leading cause of mortality of diabetic patients. Cardiovascular disease in DM involves complex pathophysiology processes, which are promoted by many risk factors. Objective: Genetic, epigenetic, lifestyle and environmental factors are responsible for the current epidemic of diabetes and the subsequent increased risk of cardiovascular disease. Over the past years, targets focusing on the increased risk of cardiovascular events in diabetic patients have attracted significant interest. Conclusion: Within this review, the roles of insulin resistance, endothelial dysfunction and lifestyle changes in the development of cardiovascular disease in diabetic patients are discussed. Potential strategies and challenges in targeting cardiovascular risks in diabetic individuals are also considered.

Background: Atherosclerosis is a chronic inflammatory disease and a major risk factor for several important cardiovascular events, particularly coronary artery disease and stroke. The pathological process of atherosclerosis is considered to be dynamic and complicated, involving interactions between various different cell types within arteries and the cells that migrate into the vessel wall. Objective: Human cellular repressor of E1A-stimulated genes (CREG) was originally identified as a transcription factor with the ability to antagonize transcriptional activation and cellular transformation induced by the adenovirus E1A oncoprotein. However, subsequent studies also identified it as a secreted glycoprotein able to sustain cellular homeostasis and withstand pathological cell and tissue damage. Results: We demonstrated that CREG may modulate homeostasis of vascular wall cells and inhibit inflammation of vascular tissue cells and macrophages, indicating a potential protective effect of CREG against inflammation. Mechanistically, CREG behaves like a typical soluble lysosomal protein that regulates the formation and maturation of lysosomes by modulating the small GTPase protein Rab7, to mediate autophagy in vascular tissue cells. Conclusion: The impact of CREG on lysosome formation may have important therapeutic significance in atherosclerosis.

Background: Cardiac tumors rare cardiac disorders with an overall incidence rate < 0.33%. Cardiac tumors can be classified as primary or secondary depending on the origins of tumors. Primary cardiac tumors (5% incidence) are rare compared with the secondary (95%, metastases of the heart) cardiac tumors. Objective: Given that cardiac tumors exhibit some nonspecific symptoms compared with other heart diseases, clinical diagnosis of cardiac tumors is rather challenging. Thus we will try to review the classification and pathogenesis of cardiac tumors. Conclusion: Current evidence revealed that 75% of cardiac tumors are considered benign (myxoma, fibromas, lipomas, rhabdomyomas, hemangiomas, teratomas, papillary fibroelastomas, pericardial cysts or cystic tumor of atrioventricular node). Clinical differential diagnosis of cardiac tumors is mainly based on imaging techniques including transthoracic and transesophageal echocardiograms, computed tomography (CT) scans and magnetic resonance imaging (MRIs). This mini-review tries to summarize recent understanding of the pathogenesis and therapeutics of cardiac tumors.

Background: The human aldehyde dehydrogenase 2 (ALDH2) is the most effective enzyme in the detoxification of alcohol metabolite acetaldehyde. The ALDH2*2 mutation is caused by a single nucleotide substitution which results in a nearly inactive form of ALDH2 enzyme. The ALDH2 genotype has been used as a surrogate of alcohol to get causal inferences of alcohol in related diseases implementing Mendelian randomization approach. In addition, ALDH2 enzyme has significant effect on different diseases, indicating the potential therapeutic value of ALDH2 regulators including both activators like Alda-1 and inhibitors such as daidzin and daidzein. Objective: In this review, we aim to systematically discuss the implications of ALDH2 genotype and ALDH2 enzyme regulators, highlighting their epidemiological and clinical importance, respectively. Conclusion: ALDH2 polymorphism is shown to be a genetic instrument for alcohol use in Mendelian randomization analysis. ALDH2 regulators exhibit potential therapeutic value as the important roles of ALDH2 in various diseases. Both the genetic polymorphism and enzyme activity regulation of ALDH2 are of great importance to their epidemiologic and clinical applications.

Background: Coronary heart disease is the leading cause of mortality and morbidity, incurring a major burden of medical care. Even with increasing application of emergent recanalization (PCI and CABG) therapy, ischemia and ischemic reperfusion injury remain as the dominant pathological process that damages cardiomyocytes. Mitochondrial Aldehyde dehydrogenase-2 (ALDH2) is a multifunctional enzyme catalyzing the oxidation of aldehydes. Objective: Accumulating data have shown that ALDH2 can help restore mitochondria function by eliminating toxic aldehyde and participating in cellular signaling important for cell adaption and survival. This article reviews the biology and pathobiology roles of ALDH2 in the ischemic cardiovascular disease, focusing on the genetic evidence associated with the oriental patients. Conclusion: The ALDH2*2 mutant allele (deficiency genotype) is present in nearly half of the East Asian population. Development of a safe way to restore ALDH2 function in this population thus has unique clinical implication.