Abstract
Vascular smooth muscle cell proliferation has been known to be predominant in vascular remodeling of pulmonary hypertensive. The GATA family proteins, a group of zinc finger transcription factors, play an important role during cell proliferation. The aim of present study was to investigate the expression of GATA-6 gene in experimental pulmonary hypertensive rats and explore the effect of regulation of GATA-6 expression by simvastatin on pulmonary vascular remodeling. The male Sprague-Dawley rats model was established with receiving pneumonectomy and monocrotaline (MCT) administration. Right pulmonary artery remodeling in these animals was compared with untreated rats or rats receiving simvastatin. The level of GATA-6 mRNA and protein expression was detected by reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, respectively. Pneumonectomized, MCT-treated rats had significantly increased mean pulmonary arterial pressure (mPAP), RV/(LV + S) ratio (ratio of the right ventricular to left ventricular and septum weights), vascular occlusion scores (VOSs), and percent media wall thickness on day 35, all the indices were significantly decreased after simvastatin administration in these rats. The level of GATA-6 mRNA and protein were markedly decreased in these pneumonectomy and MCT-treated rats, and they were significantly up-regulated in these rats after receiving simvastatin. These results indicate that the development and progression of pulmonary hypertension is prevented by simvastatin by up-regulating GATA-6 expression in the lung tissue.
Highlights
Hypertensive pulmonary vascular disease is characterized by pulmonary vascular remodeling, involving abnormal proliferation of vascular endothelial and smooth muscle cells and extracellular matrix deposition, leading to occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular failure, and death
Pneumonectomized, MCT-treated rats had significantly increased mean pulmonary arterial pressure, RV/(LV + S) ratio, vascular occlusion scores (VOSs), and percent media wall thickness on day 35, all the indices were significantly decreased after simvastatin administration in these rats
The level of GATA-6 mRNA and protein were markedly decreased in these pneumonectomy and MCT-treated rats, and they were significantly up-regulated in these rats after receiving simvastatin
Summary
Hypertensive pulmonary vascular disease is characterized by pulmonary vascular remodeling, involving abnormal proliferation of vascular endothelial and smooth muscle cells and extracellular matrix deposition, leading to occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular failure, and death. An unbiased microarray screen of genes regulated by GATA-6 in VSMCs identifies that endothelin-1 and angiotensin 1a (AT1a) receptor genes are direct GATA-6 target genes [23] Based on these studies, we speculate that activity of transcription factor GATA-6 may be regulated by disturbed laminar shear stresses occurring in pulmonary hypertension. Statins can suppress endothelial and vascular smooth muscle cell proliferative and inflammatory responses to injury [27, 28] These effects involve inhibition of isoprenylation of Rho and Rac family GTPases that couple growth factor receptors to the intracellular mitogen-activated protein/extracellular signal-regulated kinase (MAP/ERK) kinase signaling pathways and induction of the cell cycle inhibitor p27Kip 1 [27, 28]. We showed that the expression of GATA-6 mRNA and protein was downregulated in this pulmonary hypertension model, which was reversed by simvastatin administration
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