ALTERED PROSTAGLANDIN SYNTHASE EXPRESSION IN THE DEVELOPMENT OF PULMONARY ARTERIAL HYPERTENSION: POTENTIAL THERAPEUTIC TARGETS

Objective: Prostaglandins play a key role in inflammation, vasoconstriction, and remodelling. We hypothesized prostaglandin synthases are also involved in development of pulmonary arterial hypertension (PAH). Design and method: Monocrotaline (MCT; 60 mg/kg, s.c.) or vehicle (CON) were administered to Wistar rats to induce PAH. Rats were sacrificed one (MCT1W), two (MCT2W), or four weeks (MCT4W) after treatment, with prematurely terminated rats (ptMCT) sacrificed earlier due to severe PAH. Expressions of cyclooxygenase 2 (Cox2), prostaglandin I2 synthase (Ptgis), thromboxane A synthase 1 (Tbxas1), microsomal prostaglandin E synthase (Ptges), prostaglandin D2 synthase (Ptgds), hematopoietic prostaglandin D synthase (Hpgds), prostaglandin F synthase (Prxl2b), were determined by RT-qPCR in lungs, right ventricle (RV) and left ventricle (LV). Results: Lung weight increased at 2 and 4 weeks (p<0.05), RV weight was elevated after 4 weeks (p<0.05), indicating developed PAH and organ damage. LV weight wasn’t altered. We observed decreased hemoglobin oxygen saturation and elevated respiratory and heart rate after 4 weeks (p<0.05). Gene expression of Cox2 increased after four weeks in the lungs (p<0.05), and markedly increased in the LV and RV in MCT4W (p<0.05) and ptMCT (p<0.05). Ptgis was decreased in RV and LV in MCT1W (p<0.05) and increased after 4 weeks in RV (p<0.05) and lung (p<0.05). Tbxas1 was markedly elevated after 4 weeks in the RV (p<0.05). Ptges was elevated in the lung of terminally ill rats (p<0.05). Ptgds was decreased in LV of MCT1W (p<0.05), increased in MCT2W in LV (p<0.05). In RV, downregulation of Ptgds was observed after 1 and 2 weeks (p<0.05), followed by elevation after 4 weeks (p<0.05). Hpgds was only upregulated in the LV of ptMCT (p<0.05). Prxl2b was downregulated in the LV in ptMCT (p<0.05). Conclusions: Downregulations of Ptgis and Ptgds precede the development of RV damage that is associated with possibly compensatory elevations of these genes. Tbxas1 and Ptges could be potential therapeutic targets in PAH. However, functional validation is necessary to confirm their roles in disease progression and therapeutic viability.