title: The extracellular signal-regulated kinase is involved in the effects of sildenafil on pulmonary vascular remodeling.
abstract: Pulmonary hypertension is a group of diseases comprising vascular constriction and obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, for example, sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats. We investigate the mechanisms of sildenafil on the pulmonary vascular remodeling of pulmonary hypertension induced by monocrotaline (MCT) in rats. Thirty Sprague-Dawley rats (weighing 200-220 g) were administered with MCT abdominal cavity injection or equivalent volume of normal saline (NS) (which were treated as C group n = 10) to induce pulmonary hypertension model. Fourteen days later, 20 MCT treated rats were randomly fed with sildenafil (25mg/kg/day) or placebo as S, P group (10 rats for each group), respectively. Another 6 weeks later, mean pulmonary artery pressure (mPAP), index of right ventricular hypertrophy (RV/LV+S) of all animals were measured under general anesthesia. Pulmonary tissue was collected to investigate pathological features of pulmonary arteries and to measure protein expression of ERK(1)/ERK(2) and MKP1. After 6 weeks, there were significant elevated mPAP and RV/LV+S in both P and S groups. The ratio of wall thickness to vessel diameter in pulmonary arteries with diameters <200 microm were increased in both P and S groups. But the ratio of wall thickness to vessel diameter was smaller in S group than that in P group. The phosphorylation level of ERK(1)/ERK(2) were elevated in both P and S groups, but the level of phosphorlation ERK(1)/ERK(2) were lower in S group than that in P group. Intriguingly, the expression level of MKP1 was significantly increased in both S and P groups, while it was higher in S group than that in P group. The sildenafil can decrease mPAP and inhibit the progress of pulmonary vascular remodeling in pulmonary hypertension rats. The ERK-MAP kinase signaling pathway might play a role during this process.
authors.affiliation: Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China. zz73cxf199@yahoo.com.cn
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zeng
authors.forename: Yingchuan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jiang
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Wang
authors.forename: BingBing
authors.initials: B
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016686:Monocrotaline; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000199:Actins; D000959:Antihypertensive Agents; D054638:Dual Specificity Phosphatase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016686:Monocrotaline; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents; C498862:Acta2 protein, rat