Effect of All-Trans-Retinoic Acid on the Development of Chronic Hypoxia-Induced Pulmonary Hypertension

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp nder all conditions causing pulmonary hypertension (PH), vascular changes include the new muscularization of normally non-muscular peripheral pulmonary arteries and medial hypertrophy of muscular arteries. 1-8 Plasma levels of all-trans-retinoic acid (ATRA) and 13-cis retinoic acid are reduced in patients with idiopathic PH compared to control subjects. 9 ATRA treatment ameliorated the rise in pulmonary artery pressure (PAP) in monocrotalineinduced PH in rats. 10 Some of the steps to progressive fibrosis in monocrotaline-induced PH could be interrupted by retinoic acid treatment. 11 According to these studies, ATRA treatment might also ameliorate the development of another model of PH, that is, chronic hypoxia-induced PH.Retinoic acid reduces the proliferation of cultured vascular smooth muscle cells in vitro. 12 Platelet-derived growth factor-BB and serum-stimulated rat aortic smooth muscle cell DNA syntheses and cell proliferation in culture were also inhibited by retinoic acid. 13 In addition, supplemental retinoid reduces neointimal formation in the rat carotid artery after balloon withdrawal injury. 14 A recent study showed that ATRA increases nitric oxide (NO) synthesis by endothelial cells. 15 The upregulation of NO synthase (NOS) by ATRA has been shown in cultured vascular endothelial cells 16 and coronary arteries in chronic kidney disease. 17 We previously showed that the NO precursor L-arginine reduced the development of PH and vascular remodeling in monocrotalineinduced PH and chronic hypoxia-induced PH rats. 2 Continuously inhaled NO also prevented the development of PH in the latter rats. 3 Thus, retinoic acid might reduce the development of PH directly through cell growth inhibition or indirectly through the production of NO. Therefore, we designed this study to determine if ATRA prevents the development of PH and hypertensive pulmonary vascular changes in chronic hypoxia-induced PH in rats. MethodsThe Animal Experiment Committee of Mie University School Background: An earlier study showed that all-trans-retinoic acid (ATRA) prevents the development of monocrotalin-induced pulmonary hypertension (PH). The purpose of the present study was to determine the effect of ATRA on another model of chronic hypoxia-induced PH.

Effects of Autologous Bone Marrow Mononuclear Cells Implantation in Canine Model of Pulmonary Hypertension

“…The MCT-induced PH model is known to present similar pathology to that of primary PH. 34 In the present study, 2 weeks after well-established PH by intravenous injection of 3 mg/kg DMCT via the RA, 35 we intratracheally administered 1-3×10 7 labeled ABMMNCs and investigated the effect on DMCT-induced PH 6 weeks later. We found that the injection of ABM-MNCs into dogs with PH had beneficial effects on the lungs and heart, such as the hemodynamic data (PVR, sPAP, mPAP and PAWP), which were significantly improved, and the RV/(LV+S) weight ratio, which was significantly lower in the ABM-MNCs group compared with the PH group.…”

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

“…Importantly, ATRA has been shown to decrease collagen deposition in the rat monocrotaline model of pulmonary hypertension [178]. Decreased muscularization of resistant pulmonary arteries has also been demonstrated with ATRA administration in this model [179], although not always associated with a decrease in the pulmonary hypertension phenotype [180]. …”

Nitric Oxide in Pathophysiology and Treatment of Pulmonary Hypertension

“…These results suggest that ATRA might prevent the development of experimental PH in rats. ATRA ameliorated the development of MCT-induced PH [108], but not chronic hypoxia-induced PH [109]. These differences in the effect of ATRA on the development of PH may be due to a more pronounced inflammatory response in MCT-induced PH and a more subtle inflammatory reaction in chronic hypoxia-induced PH; endothelial damage precedes the rise in PAP in MCT model whereas the rise in PAP precedes endothelial changes in the chronic hypoxic model [110,111].…”