[Expression of connective tissue growth factor and its down-regulation by simvastatin administration in pulmonary...

To explore the role of expression of connective tissue growth factor (CTGF) in pulmonary vascular remodeling of pulmonary hypertensive rats, and investigate the regulation of CTGF expression by simvastatin in this animal model.

Eighty male Sprague-Dawley rats (350 to 400 g) were randomized to 7 groups. The rats in group PM(1 - 21) (n = 10) and PM(1 - 35) (n = 12) were treated with pneumonectomy + monocrotaline (MCT), and sacrificed at the 21st or 35th experimental day;those in groups PMS(1 - 35) (n = 12), PMS(21 - 35) (n = 12), PMV(1 - 35) (n = 12) and PMV(21 - 35) (n = 12) were given daily lavage of simvastatin (or vehicle) as intervention measure which began from the 1st and 21st experimental days, respectively; additional 10 rats were used as control without any intervention. The animals were sacrificed at the end of experiment (35 th day) as hemodynamic measurements and study on the morphological parameters relevant to pulmonary vascular remodeling were performed on each group of rats. The expression of ET-1 mRNA, CTGF mRNA and protein, and synthesis of collagen in these pneumonectomized, MCT-treated rats were compared between control and rats treated with simvastatin.

Rats in PM(1 - 35) Group developed severe PAH (mPAP = 39.75 +/- 3.62 mm Hg) (1 mm Hg = 0.133 kPa), right ventricular hypertrophy [RV/(LV + S) ratio = 0.627 +/- 0.040], and arterial medial hypertrophy (WT% = 61.73 +/- 5.39), these parameters of the control animals were 17.10 +/- 1.20 mm Hg, 0.262 +/- 0.018 and 14.71 +/- 1.16, respectively. CTGF mRNA and protein were mainly located in pulmonary arterial smooth muscle cells and interstitial macrophage shown by in situ hybridization and immunohistochemistry, respectively. The expression of ET-1 mRNA and CTGF mRNA detected by fluorescent quantitative RT-PCR in Group PM(1 - 35) were significantly increased in comparison with controls, and so did the CTGF protein expression determined by Western blotting in these diseased rats. The content of hydroxyproline (1.30 +/- 0.19 microg/mg wet lung) was remarkably higher than that of control animals (0.56 +/- 0.10 microg/mg wet lung). The up-regulation of ET-1 and CTGF gene expression, and elevated synthesis of hydroxyproline were reversed in rats intervened with simvastatin. The pulmonary hypertension, right ventricular hypertrophy and medial hypertrophy were attenuated in all simvastatin-treated rats no matter the intervention was initiated from the beginning or midway of the study.

The up-regulation of CTGF gene expression may play an important role in the development of pulmonary vascular remodeling in PAH. Simvastatin can prevent and, to some extent, reverse the vascular remodeling via down-regulation of CTGF gene expression.