Role of carbonic anhydrases 9 and 12 in hypoxia and non-hypoxia associated pulmonary hypertension
Aleksandar Petrovic, Oleg Pak, Jan Niklas Schneider, Jan Ewert, Franz Loeffler, Daniel Gerd Bermes, Astrid Weiss, Christina Pilz, Stefan Hadzic, Marija Gredic, Cheng-Yu Wu, Simon Platzek, Argen Mamazhakypov, Akylbek Sydykov, Khodr Tello, Natascha Sommer, Akpay Sarybaev, Sergey Avdeev, Clemens Ruppert, Andreas Günther, Norbert Weissmann, Hossein Ardeschir Ghofrani, Djuro Kosanovic, Ralph Theo SchermulyAbstract
RATIONALE
Pulmonary hypertension (PH) is characterized by several cancer-like attributes, such as dysregulated proliferation and migration of pulmonary vascular cells. Carbonic anhydrases (CA)9 and 12 are elevated in various types of tumor tissues and play a major role in the pH regulation system of cancer cells. CA9 and 12 engagement in the pathology of PH remains unclear.
METHODS
Lung tissue samples from PH patients were analyzed for CA9 and 12 expression profiles. Circulating CA9 levels were measured in the plasma of PH patients and Kyrgyz highlanders. In vitro expression and functional studies were conducted in pulmonary arterial smooth muscle cells (PASMCs). Finally, two in vivo studies were carried out to investigate the therapeutic potential of the specific CA9 and 12 inhibitor S4.
RESULTS
The mRNA and protein expression of CA9 and 12 were upregulated in lungs of PH patients and during hypoxic and non-hypoxic stimulation of PASMCs. Circulating CA9 levels were elevated in both PH patients and Kyrgyz highlanders with PH. Furthermore, CA9 and 12 played an important role in the proliferation and migration of PASMCs. Our study demonstrated that CA9 and 12 are crucial for maintaining pH homeostasis in PASMCs and, subsequently, for the activation of protein kinases. Finally, pharmacological inhibition of CA9 and 12 ameliorated the development of monocrotaline-induced PH in rats and chronic hypoxia-induced PH in mice.
CONCLUSIONS
Our study provides evidence that CA9 and 12 are engaged in the pathogenesis of hypoxia and non-hypoxia associated PH and may represent novel therapeutic targets in future.