Abstract
BackgroundPreventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats.MethodsFifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed.ResultsmPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats.ConclusionsWe found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.
Highlights
Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH)
Because 1 CLZ increases Serine-threonine protein kinase (AKT) phosphorylation in cell-based studies [38, 40], 2 PI3/AKT-dependent Nitric oxide (NO) production has been reported [38, 55], and 3 NO production and/or administration ameliorates the development of hypertensive pulmonary vascular changes [6, 7, 33], we determined the levels of the AKT, phosphorylated AKT (pAKT), endothelial nitric oxide synthase (eNOS) mRNA, eNOS, and phosphorylated eNOS (peNOS) proteins
Technical issues might exist, we did not detect a decrease in right ventricle fibrosis based on collagen staining in CLZ-treated MCT rats, which might suggest that CLZ does not correct fibrosis
Summary
Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Pulmonary hypertension (PH) is characterized by an increase in pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), and functional and/ or structural vascular changes [1, 2]. Possible causes of PH include pulmonary vasoconstriction, diffuse microthromboembolism, and pulmonary vascular remodeling [1,2,3]. In all conditions causing PH in humans [3,4,5] and experimental models [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20], vascular changes include new muscularization of normally nonmuscular peripheral pulmonary arteries and medial hypertrophy of muscular arteries. We and other researchers have shown that modulators that increase NO production ameliorate the development of PH and vascular remodeling [6, 7, 33]
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