Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Despite the extensive knowledge in cell physiology, biology and pharmacology of the heart, several changes of contracting heart cells’ normal functioning did not permit to prevent or treat some heart diseases. Such a problem is due, in part, to our negligence at the anatomical level in considering that the heart is not only constituted of contracting cardiomyocytes. Our group reported for the first time that the cells covering the heart ventricular cavities play an important role in the regulation of heart function. Thus, these cells should be considered as a pharmacological target to restore the normal heart function. Therefore, it is extremely important to understand the normal physiological, biological and pharmacological characteristics of these heart cells, called endocardial endothelial cells (EECs), which secrete many cardioactive factors. In addition, our negligence is also due to the lack of consideration that receptors, channels, exchangers and pumps are not only be present at the cell membrane but can also be found at other membranes inside the cell such as those of the nucleus. Our work reported for the first time that the nucleus could be considered as a cell within the cell and it contains structures, similar to those of its host cell, that were called nuclear nuclear T-tubules (NTTs) and nucleoplasmic reticulum (NR). In addition, we demonstrated that the membranes of these nuclear structures do contain, as the plasma membrane, channels, exchangers, pumps and receptors including those activated by factors released by EECs such as endothelin-1 (ET-1). Therefore, it is extremely important to understand the EECs physiology, biology and pharmacology in order to better understand the normal heart function. In addition, it is important to understand the contribution of intracellular structures present in the nucleus, such as the NTTs, in order to better understand their contribution to EECs secretory function. Thus, our overall research program is to test the hypothesis that EECs are major contributors to normal heart function and that factors released by these cells such as ET-1 regulate, via activation of its receptors present at both the plasma, nuclear and NTT membranes. This research program will also help us to further support our major hypothesis that abnormal physiological function of EECs, and more particularly of NTTs’ ET-1 receptors, is at the ‘heart’ of some abnormal heart problems.