Author Description

How does Ca2+ as a common second messenger in the heart conduct specific, even inverse signals, in response to various stimuli? In order to address this question, researchers have studied Ca2+ signaling networks for decades to decipher the complexity. This dissertation aimed to demonstrate specific Ca2+ roles in various cellular compartments in cardiomyocytes under both physiological and pathological conditions. For the first part of this dissertation, I focused on multifunctional Ca2+/calmodulin dependent kinase II (CaMKII) roles in cardiomyocytes with acute hyperglycemia. This work has been published in Circulation Research and was highlighted by an editorial review. To elucidate the role of Ca2+ in connecting the upstream extracellular high glucose stimulus to distinct responses, different transgenic mouse models were studied to identify the immediate downstream effectors. Our results showed that CaMKII can be activated via Ca2+/CaM binding and O-GlcNAcylation within several minutes of high glucose exposure in cardiomyocytes. Subsequently, CaMKII activates NADPH oxidase 2 (NOX2) leading to reactive oxygen species (ROS) production in cytosol. In contrast, mitochondria, which are also known as a major ROS producing site in cardiomyocytes were not the source of hyperglycemia-induced ROS production. Even though acute high glucose did not provoke a mitochondria ROS response, Ca2+ has been shown to play an essential role in mitochondrial ROS production, energetic, metabolic and apoptotic regulation. In Chapter III and IV, we investigated Ca2+ handling in mitochondria and its role in pathological models. In collaboration with Dr Molkentin's group, we found that the mitochondria calcium uniporter b (MCUb) could dominantly abolish acute Ca2+ uptake mediated by MCU (its homolog). This unique property was shown to be protective against ischemia-reperfusion injury. To further strengthen our understanding of mitochondrial Ca2+ regulation, we focused on the major efflux pathwa