title: Dasatinib Attenuates Pressure Overload Induced Cardiac Fibrosis in a Murine Transverse Aortic Constriction Model.
abstract: Reactive cardiac fibrosis resulting from chronic pressure overload (PO) compromises ventricular function and contributes to congestive heart failure. We explored whether nonreceptor tyrosine kinases (NTKs) play a key role in fibrosis by activating cardiac fibroblasts (CFb), and could potentially serve as a target to reduce PO-induced cardiac fibrosis. Our studies were carried out in PO mouse myocardium induced by transverse aortic constriction (TAC). Administration of a tyrosine kinase inhibitor, dasatinib, via an intraperitoneally implanted mini-osmotic pump at 0.44 mg/kg/day reduced PO-induced accumulation of extracellular matrix (ECM) proteins and improved left ventricular geometry and function. Furthermore, dasatinib treatment inhibited NTK activation (primarily Pyk2 and Fak) and reduced the level of FSP1 positive cells in the PO myocardium. In vitro studies using cultured mouse CFb showed that dasatinib treatment at 50 nM reduced: (i) extracellular accumulation of both collagen and fibronectin, (ii) both basal and PDGF-stimulated activation of Pyk2, (iii) nuclear accumulation of Ki67, SKP2 and histone-H2B and (iv) PDGF-stimulated CFb proliferation and migration. However, dasatinib did not affect cardiomyocyte morphologies in either the ventricular tissue after in vivo administration or in isolated cells after in vitro treatment. Mass spectrometric quantification of dasatinib in cultured cells indicated that the uptake of dasatinib by CFb was greater that that taken up by cardiomyocytes. Dasatinib treatment primarily suppressed PDGF but not insulin-stimulated signaling (Erk versus Akt activation) in both CFb and cardiomyocytes. These data indicate that dasatinib treatment at lower doses than that used in chemotherapy has the capacity to reduce hypertrophy-associated fibrosis and improve ventricular function.
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Sundaravadivel
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Dorea L
authors.initials: DL
authors.lastname: Pleasant
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Harinath
authors.initials: H
authors.lastname: Kasiganesan
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Lakeya
authors.initials: L
authors.lastname: Quinones
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Kamala P
authors.initials: KP
authors.lastname: Sundararaj
authors.affiliation: Dublin City University, Dublin 9, Ireland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Roche
authors.affiliation: Dublin City University, Dublin 9, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Connor
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Bradshaw
authors.affiliation: Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, South Carolina, United States of America.
authors.forename: Dhandapani
authors.initials: D
authors.lastname: Kuppuswamy
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001011:Aorta; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003250:Constriction; D000069439:Dasatinib / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011312:Pressure / Q000009:adverse effects*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D015415:Biomarkers; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496051:Ptk2 protein, mouse; D000069439:Dasatinib