ABSTRACT
Atherosclerosis is considered a chronic inflammatory disease of the arterial wall. Recently, compelling evidence has arisen for the role of monocytes and neutrophils and a particular protein complex that resides within these cells - the NLRP3 inflammasome - in atherosclerosis-associated inflammation. It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1ß and interleukin 18 - key mediators in the inflammatory cascade that drive plaque progression and instability. In this review, we describe the role of monocytes/macrophages and neutrophils in atherosclerosis, outline mechanisms of activation of the NLRP3 inflammasome in the setting of atherosclerosis-associated inflammation and discuss potential therapies that specifically target the NLRP3 inflammasome and/or its downstream mediators in atherosclerosis, with a particular focus on the emerging role of colchicine.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arteries/drug effects , Atherosclerosis/drug therapy , Colchicine/therapeutic use , Inflammasomes/antagonists & inhibitors , Inflammation/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Animals , Arteries/metabolism , Arteries/pathology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cytokines/metabolism , Humans , Inflammasomes/metabolism , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/metabolism , Macrophages/drug effects , Macrophages/metabolism , Monocytes/drug effects , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Plaque, Atherosclerotic , Signal Transduction/drug effectsABSTRACT
Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability. Here we investigated the effect of Doxo 1uM for 24h of stimulation on cultured neonatal rat cardiomyocytes. We showed that Doxo inhibits basal autophagy. This inhibition is due to both Akt/mTOR signaling pathway activation and Beclin 1 level decrease. To assess the role of autophagy on Doxo-induced cardiomyocyte death, we evaluated the effects 3-methyladenine (3-MA), bafilomycin A1 (BafA), siRNA Beclin 1 (siBeclin 1) and rapamycin (Rapa) on cell viability. Inhibition of autophagy with 3-MA, BafA and siBeclin 1 increased lactate dehydrogenase (LDH) release but, when autophagy was induced by Rapa, Doxo-induced cardiomyocyte death was decreased. These results suggest that Doxo inhibits basal autophagy and contributes to cardiomyocyte death. Activation of autophagy could be used as a strategy to protect the heart against Doxo toxicity.
Subject(s)
Antibiotics, Antineoplastic/toxicity , Autophagy , Cardiotoxins/toxicity , Doxorubicin/toxicity , Myocytes, Cardiac/drug effects , Adenine/analogs & derivatives , Adenine/pharmacology , Animals , Apoptosis/drug effects , Beclin-1/genetics , Beclin-1/metabolism , Cell Survival/drug effects , L-Lactate Dehydrogenase/metabolism , Macrolides/pharmacology , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Myocytes, Cardiac/cytology , Rats , Signal Transduction , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
The coronary microcirculation plays a critical role in normal cardiac physiology as well as in many disease states. However, methods to evaluate the function of the coronary microvessels have been limited by technical and theoretical issues. Recently, the index of microcirculatory resistance (IMR) has been proposed and validated as a simple and specific invasive method of assessing the coronary microcirculation. By relying on the thermodilution theory and using a pressure-temperature sensor guidewire, IMR provides a measurement of the minimum achievable microcirculatory resistance in a target coronary artery territory, enabling a quantitative assessment of the microvascular integrity. Unlike indices such as coronary flow reserve, IMR is highly reproducible and independent of hemodynamic changes. In ST-elevation myocardial infarction, IMR predicts myocardial recovery and long-term mortality, whereas in patients with stable coronary artery disease, preintervention IMR predicts the occurrence of periprocedural myocardial infarction. Increasingly, research has focused on IMR-guided interventions of the microcirculation, with the aim of preventing and/or treating the microcirculatory dysfunction that commonly accompanies the epicardial coronary disease. In the present review, we will discuss the theoretical and practical basis for IMR, the clinical studies supporting it, and the future lines of research using this novel tool.