Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Clin Invest. 2010 Feb;120(2):472-84. doi: 10.1172/JCI39434. Epub 2010 Jan 11.
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.
PDGFR 是新型抗癌治疗的重要靶点，因为它在多种恶性肿瘤中过度表达。然而，最近几种抑制 PDGFR 信号的抗癌药物与临床心力衰竭有关。由于 PDGFR 信号在心脏中的作用在很大程度上仍未得到探索，因此理解 PDGFR 抑制剂的这种作用一直很困难。如本文所述，我们发现暴露于负荷诱导的心脏应激的小鼠心脏中 PDGFR-β的表达和激活显著增加。在心脏发育或成年期敲除 Pdgfrb 的小鼠中，暴露于负荷诱导的应激会导致心脏功能障碍和心力衰竭。从机制上讲，我们表明心肌细胞 PDGFR-β信号在应激诱导的心脏血管生成中起着至关重要的作用。具体而言，我们证明了心肌细胞 PDGFR-β是应激诱导的心肌细胞旁分泌血管生成能力（血管生成潜能）的必需上游调节剂。这些结果表明，心肌细胞 PDGFR-β是对压力超负荷诱导的应激的代偿性心脏反应的调节剂。此外，我们的发现可能为抗癌 PDGFR 抑制剂引起的心脏毒性的机制提供一些见解。
