Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.
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.
Chintalgattu
Vishnu
V
Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ai
Di
D
Langley
Robert R
RR
Zhang
Jianhu
J
Bankson
James A
JA
Shih
Tiffany L
TL
Reddy
Anilkumar K
AK
Coombes
Kevin R
KR
Daher
Iyad N
IN
Pati
Shibani
S
Patel
Shalin S
SS
Pocius
Jennifer S
JS
Taffet
George E
GE
Buja
L Maximillian
LM
Entman
Mark L
ML
Khakoo
Aarif Y
AY
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
D020797:Receptor, Platelet-Derived Growth Factor beta