Simvastatin prevents and reverses chronic pulmonary hypertension in newborn rats via pleiotropic inhibition of RhoA signaling.
Chronic neonatal pulmonary hypertension (PHT) frequently results in early death. Systemically administered Rho-kinase (ROCK) inhibitors prevent and reverse chronic PHT in neonatal rats, but at the cost of severe adverse effects, including systemic hypotension and growth restriction. Simvastatin has pleiotropic inhibitory effects on isoprenoid intermediates that may limit activity of RhoA, which signals upstream of ROCK. We therefore hypothesized that statin treatment would safely limit pulmonary vascular RhoA activity and prevent and reverse experimental chronic neonatal PHT via downstream inhibitory effects on pathological ROCK activity. Sprague-Dawley rats in normoxia (room air) or moderate normobaric hypoxia (13% O2) received simvastatin (2 mg·kg-1·day-1ip) or vehicle from postnatal days 1-14 (prevention protocol) or from days 14-21 (rescue protocol). Chronic hypoxia increased RhoA and ROCK activity in lung tissue. Simvastatin reduced lung content of the isoprenoid intermediate farnesyl pyrophosphate and decreased RhoA/ROCK signaling in the hypoxia-exposed lung. Preventive or rescue treatment of chronic hypoxia-exposed animals with simvastatin decreased pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary arterial remodeling. Preventive simvastatin treatment improved weight gain, did not lower systemic blood pressure, and did not cause apparent toxic effects on skeletal muscle, liver or brain. Rescue therapy with simvastatin improved exercise capacity. We conclude that simvastatin limits RhoA/ROCK activity in the chronic hypoxia-exposed lung, thus preventing or ameliorating hemodynamic and structural markers of chronic PHT and improving long-term outcome, without causing adverse effects.
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Mathew J
MJ
Wong
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Crystal
C
Kantores
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Julijana
J
Ivanovska
Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada.|Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Amish
A
Jain
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; robert.jankov@sickkids.ca.|Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada.|Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Robert P
RP
Jankov
D000818:Animals; D000831:Animals, Newborn; D053898:Biosynthetic Pathways / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002908:Chronic Disease; D005260:Female; D006976:Hypertension, Pulmonary / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control*; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000188:drug therapy; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D066253:Vascular Remodeling / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
Rho-kinase; chronic lung injury; echocardiography; isoprenoid intermediates