Dysregulated Calcium Signaling in Cardiomyocytes--From Diabetic Atrial Fibrillation to Chemotherapy-Induced Cardiac Hypertrophy

摘要

Ca2+ is a vital second messenger in cardiomyocytes and controls excitationcontraction coupling. It also regulates cell cycle, apoptosis, hypertrophy and downstream gene transcription in the heart remodeling. Calcium homeostasis is a complicated network and the intracellular Ca2+ signaling is composed of different Ca2+ movements like Ca2+ spikes [1], waves and oscillations [2-4].The spatially-temporally regulated Ca2+ signaling is orchestrated with the Ca2+ release through ryanodine receptor (RyR) or IP3 receptor (IP3R) from Ca2+ stores such as sarcoplasmic/endoplasmic reticulum (SR/ER), recycling of Ca2+ from cell plasma back to the ER and Ca2+ influx through plasma membrane (PM) from extracellular space. There are many channels and transporters responsible for the intracellular Ca2+ homeostasis in cardiomyocytes.Firstly, the RyR mediates Ca2+ release from SR/ER [5].Secondly, the ER/SR Ca2+-ATPase (SERCA) pumps Ca2+ from the cytosol back into the ER/SR. Plasma membrane Ca2+-ATPase (PMCA) drives Ca2+ from the cytosol to the extracellular space [6].Thirdly, the Ca2+ channels or transporters located on the cell membrane allow Ca2+ influx across the plasma membrane (PM) from the extracellular space. These channels or transporters include voltage-gated Ca2+ channel (VGCC), transient receptor potential channel (TRP), store-operated calcium entry (SOCE) or Ca2+ release activated Ca2+ channel (CRAC), Na+/Ca2+ exchanger (NCX) and purinergic receptor.Fourthly, mitochondrial Ca2+ uniporter (MCU) regulates mitochondrial Ca2+ uptake. Besides, there are more channels or transporters on the cell membrane and the ER membrane involved in the regulation of intracellular Ca2+ homeostasis. The dysregulation of intracellular Ca2+ can lead to a wide spectrum of cardiovascular diseases, including but not limited to arrhythmias, cardiac hypertrophy, cardiomyopathy and heart failure (summarized in the following illustrative figure). The first chapter of this dissertation is devoted to a literature review on the intracellular Ca2+ in the cardiac system with particular emphasis on SOCE and its machinery components. In Chapter 2, the IP3-mediated disrupted calcium homeostasis in type 2 diabetes (T2DM) and atrial fibrillation (AF) is examined. In Chapter 3, the role of SOCE in chemotherapy drug epirubicin induced cardiotoxicity is investigated. Finally, in Chapter 4, conclusion will be stated and future directions will be discussed.