title: Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling.
abstract: BACKGROUND
  Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling.
  
  
  METHODS
  We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1mg/kg, 5mg/kg and 10mg/kg/day) or sorafenib (10mg/kg/day). PAB rats were treated with vehicle, sunitinib (10mg/kg/day) or sorafenib (10mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry.
  
  
  RESULTS
  Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function.
  
  
  CONCLUSIONS
  We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Germany.
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.forename: Akylbek
authors.initials: A
authors.lastname: Sydykov
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Himal
authors.initials: H
authors.lastname: Luitel
authors.forename: Bhola K
authors.initials: BK
authors.lastname: Dahal
authors.forename: Djuro
authors.initials: D
authors.lastname: Kosanovic
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.forename: Matthaeus
authors.initials: M
authors.lastname: Majewski
authors.forename: Christin
authors.initials: C
authors.lastname: Baumann
authors.forename: Steve
authors.initials: S
authors.lastname: Evans
authors.forename: Peter
authors.initials: P
authors.lastname: Phillips
authors.forename: David
authors.initials: D
authors.lastname: Fairman
authors.forename: Neil
authors.initials: N
authors.lastname: Davie
authors.forename: Chris
authors.initials: C
authors.lastname: Wayman
authors.forename: Iain
authors.initials: I
authors.lastname: Kilty
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D000077210:Sunitinib; D016278:Ventricular Function, Right / Q000187:drug effects* / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib