GRK 2338 Seminar - Andrea Olschewski

Title: POTASSIUM AND CHLORIDE CHANNELS IN PULMONARY VASCULAR DISEASES: DO WE HAVE NEW THERAPEUTIC TARGETS?

The pulmonary circulation is unique compared with systemic vascular beds. During normoxic conditions, the pulmonary circulation is at low pressure and vasodilated — compared with the high-pressure systemic circulation. The high flow favors pulmonary gas exchange and the low pressure allows the right ventricle to operate at low energy cost. The low resting vascular tone is maintained by the concerted action of ion channels, exchangers and pumps. Under physiological as well as pathophysiological conditions, they are targets of locally secreted or circulating vasodilators and/or vasoconstrictors, leading to changes in expression or to posttranslational modifications. Our investigations focus on potassium and chloride channels in the pulmonary vasculature and on their pathophysiological contribution to pulmonary hypertension (PH), a multi-factorial, progressive disease with substantial mortality and morbidity.
We have described the two-pore domain TASK-1 in primary human pulmonary artery smooth muscle cells (PASMC) and showed that TASK-1 is inhibited by hypoxia and endothelin-1, factors contributing to the pathologic mechanisms of PH. Furthermore, TASK-1 together with its endogenous activator c-Src play an important role in the maintenance of a low resting tone of the PA and that any disturbance may cause PH. According to our recent investigations, in the idiopathic form of PH (IPAH), the calcium-activated chloride channel TMEM16A is strongly upregulated. Overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of a specific inhibitor reversed remodelling of established PH in animal models. Our findings suggest that inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in pulmonary arterial hypertension.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
Dept of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria

Time:

• 3.00 pm GRK 2338 Lecture
• 4.00 pm Meet the Speaker Session 

Venue:

Zoom Meeting

Host: Thomas Gudermann (P10)