Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Skofic Maurer, D.
The role of the calcium-activated chloride channel TMEM16A in the lung.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2020. pp. 160
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Olschewski Andrea
- Olschewski Horst
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- Abstract:
- Pulmonary arterial endothelial cells (PAECs) are an important source of factors maintaining homeostasis within the pulmonary vasculature. However, when dysfunctional they are also a perfectly-positioned driver of pathological development. Ion-channelome represents an essential part in this balancing act, regulating many features that maintain endothelial cell identity and their progression towards endothelial dysfunction. Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease hallmarked by dysbalanced ion-channelome and endothelial dysfunction. Traditionally K+ channels were featured in understanding the detrimental role of dysbalanced ion conductance. More recently, Cl- channels have proven to be another pathologically-relevant factor and an intriguing target. An important part of Cl- conductivity is Ca2+-activated Cl- current (CaCC), which is mainly mediated by TMEM16A, a channel associated with the maintenance of different physiological processes, however its pathological footprint has been emphasized in several pathologies, including of systemic and pulmonary vasculature. The effect of TMEM16A in the homeostasis and pathological development of endothelial dysfunction has been so far underrepresented. Within the scope of this study, we were able to extend the pathological footprint of TMEM16A demonstrating its role in the fundamental disruption of downstream signalling pathways otherwise essential to the identity of an endothelial cell. Here we report enhanced TMEM16A activity in IPAH PAECs. Upon TMEM16A overexpression in healthy primary human PAECs in vitro and in human pulmonary arteries ex vivo, we demonstrate the functional consequences of the augmented TMEM16A activity with alterations of Ca2+ dynamics and eNOS activity as well as decreased NO production, proliferation, wound-healing, tube-formation and attenuated acetylcholine-mediated relaxation of human pulmonary arteries. Thus, our results indicate that disease-associated TMEM16A activity pathologically primes healthy pulmonary arteries and ultimately causes severe deficiencies resembling of that found in pulmonary arterial hypertension.