Matrix metalloproteinases are possible targets in monocrotaline-induced pulmonary hypertension: investigation of anti-remodeling effects of alagebrium and everolimus.

OBJECTIVE:In our study, sildenafil alone and everolimus or alagebrium in combination with sildenafil were investigated in terms of their additional therapeutic and anti-remodeling activity in monocrotaline-induced pulmonary hypertension (PH) model in rats. In particular, the inter-relationships between PH and matrix metalloproteinases (MMPs) were investigated. METHODS:The pulmonary artery responses of male Sprague Dawley rats were recorded using myography, and the quantities and activities of MMPs were analyzed in homogenates of the pulmonary arteries and lungs by enzyme-linked immunosorbent assays, activity assays, and gelatin zymography techniques. RESULTS:Our results indicated that the therapeutic effects of sildenafil were accompanied by its suppressor effects on MMP activity. It was also shown that everolimus or alagebrium in combination with sildenafil showed additional regulatory effects on MMPs as well as functional responses on pulmonary artery pressure. Therefore, the enzymes in the MMP superfamily are likely to be target molecules for the treatment of PH. CONCLUSION:In conclusion, MMPs were involved in the pathogenesis of PH, and our results suggested that the addition of everolimus or alagebrium to sildenafil therapy may be beneficial in PH. Our results indicated that agents that limit pulmonary vascular hypertrophy and inflammation via their anti-remodeling effects significantly ameliorate mortality and morbidity in PH.