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Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress
Vishnu Chintalgattu, … , Mark L. Entman, Aarif Y. Khakoo
Vishnu Chintalgattu, … , Mark L. Entman, Aarif Y. Khakoo
Published January 11, 2010
Citation Information: J Clin Invest. 2010;120(2):472-484. https://doi.org/10.1172/JCI39434.
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Research Article Cardiology Article has an altmetric score of 6

Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress

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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-β 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-β signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-β was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-β 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

Vishnu Chintalgattu, Di Ai, Robert R. Langley, Jianhu Zhang, James A. Bankson, Tiffany L. Shih, Anilkumar K. Reddy, Kevin R. Coombes, Iyad N. Daher, Shibani Pati, Shalin S. Patel, Jennifer S. Pocius, George E. Taffet, L. Maximillian Buja, Mark L. Entman, Aarif Y. Khakoo

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Figure 5

Angiogenic gene expression profile correlates with defective microvascular function in inducible, cardiac-specific PDGFR-β–knockout mice upon exposure to load stress.

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Angiogenic gene expression profile correlates with defective microvascul...
(A) Pattern of change of genes of interest over time prior to and after TAC (red, PdgfrbMerCre; blue, Pdgfrbfl/fl). (B) Change of expression from baseline (ratio of PdgfrbMerCre to Pdgfrbfl/fl) of genes associated with multiple aspects of angiogenesis (n = 4 samples in each group at each time point). (C) Representative ultrasound tracings of maximal coronary flow after hyperemic stimulus prior to TAC or 14 days after TAC in control Pdgfrbfl/fl or PdgfrbMerCre mice. (D) Quantification of CFR in Pdgfrbfl/fl, MerCreMer, or PdgfrbMerCre mice (n = 7 in each group at each time point). (E) Quantification of cardiac perfusion as assessed by myocardial contrast uptake (see Methods) from 0° (anterior wall of the left ventricle) to 90° (lateral wall of left ventricle) 14 days after TAC in PdgfrbMerCre or Pdgfrbfl/fl control mice (n = 3 PdgfrbMerCre mice, n = 4 Pdgfrbfl/fl control mice). P values were determined by ANOVA, and significant differences between PdgfrbMerCre and control (Pdgfrbfl/fl and MerCreMer) mice were confirmed with Tukey’s test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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