Rosiglitazone Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats by Regulating the Extracellular Matrix Remodelling

To investigate the effect of rosiglitazone on pulmonary arterial hypertension in rats monocrotaline (60 mg/kg)-induced pulmonary arterial hypertension was developed in male Sprague Dawley rats. Pulmonary arterial hypertensive rats were given different treatments (n=8 per group), such as saline, low dose rosiglitazone (2.5 mg/kg), and high-dose rosiglitazone (5 mg/kg) via oral gavage once a d for 21 d. Sprague Dawley rats (n=8) injected subcutaneously with physiological saline were also included as the sham control (group N), which received saline as the treatment. When the 21 d treatment regimens were completed, the mean pulmonary artery pressure was measured through right heart catherization. Hematoxylin and eosin staining was done to examine the histological changes of lung tissues, with the tunica media thickness of small pulmonary arteries were evaluated by Elastin Van Gieson staining. The medial thickness relative to the vascular diameter was determined. The degree of muscularization and α-smooth muscle actin density of non-muscularized pulmonary arterioles were also assessed. The protein expression of peroxisome proliferator-activator receptor-γ, metalloproteinase matrix metallopeptidases-2 and matrix metallopeptidases-9 in lungs was studied using immunohistochemistry. The expression of peroxisome proliferator-activator receptor-γ, matrix metallopeptidases-2 and matrix metallopeptidases-9 and tissue inhibitor of metalloproteinase-1 genes in lungs was assessed using fluorescent quantitative polymerase chain reaction. The activity of matrix metallopeptidases-2 and matrix metallopeptidases-9 was determined using gelatin zymography. Treatment of pulmonary arterial hypertension rats with low-dose and high-dose rosiglitazone significantly reduced mean pulmonary artery pressure compared to saline treatment (saline 37±5, low-dose rosiglitazone 28±4 and high-dose rosiglitazone 27±4 mmHg). Rosiglitazone treatment also reduced % wall thickness compared to the control (saline, 45.5±5.5, low-dose rosiglitazone 16.7±1.7 and high-dose rosiglitazone 13.1±3.9 %). Rosiglitazone treatment also decreased muscularization and α-smooth muscle actin density of pulmonary arterioles (muscularization: saline, 67.55±2.95 %; low-dose rosiglitazone, 54.73±2.39 %; high-dose rosiglitazone, 51.74±2.67 %; α-smooth muscle actin density: saline, 0.49±0.03; low-dose, 0.38±0.03; high-dose, 0.31±0.02). Compared to the pulmonary arterial hypertension rats receiving saline alone, those treated with low-dose and high-dose rosiglitazone presented significantly higher peroxisome proliferator-activator receptor-γ expression and lower metallopeptidases-2, metallopeptidases-9 and tissue inhibitor of metalloproteinase-1 expression in lung tissues. Low-dose and high-dose rosiglitazone treatment also reduced metallopeptidases-9 activity in lung tissues compared to the saline-treated pulmonary arterial hypertension rats. Early administration of rosiglitazone might delay the progression of monocrotaline-induced pulmonary arterial hypertension in rats. The underlying mechanism could be attributed to the reactivation of peroxisome proliferatoractivator receptor-γ signaling that modulated metallopeptidases-9 activity and in turn extracellular matrix remodeling.