title: Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.
abstract: PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-beta signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-beta was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors.
authors.affiliation: Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Chintalgattu
authors.forename: Di
authors.initials: D
authors.lastname: Ai
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Jianhu
authors.initials: J
authors.lastname: Zhang
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Shih
authors.forename: Anilkumar K
authors.initials: AK
authors.lastname: Reddy
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Iyad N
authors.initials: IN
authors.lastname: Daher
authors.forename: Shibani
authors.initials: S
authors.lastname: Pati
authors.forename: Shalin S
authors.initials: SS
authors.lastname: Patel
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pocius
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: L Maximillian
authors.initials: LM
authors.lastname: Buja
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Aarif Y
authors.initials: AY
authors.lastname: Khakoo
mesh_terms: D000818:Animals; D001835:Body Weight; D003326:Coronary Circulation; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D009929:Organ Size; D010766:Phosphorylation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013318:Stroke Volume; D016474:Weight-Bearing
chemical_list: D020797:Receptor, Platelet-Derived Growth Factor beta