Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress
Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress
复制标题
DOI：
10.1172/jci39434
复制
发表时间：
2010-02-01
影响因子：
15.9
通讯作者：
Khakoo, Aarif Y.
中科院分区：
文献类型：
--
作者：
Chintalgattu, Vishnu;Ai, Di;Khakoo, Aarif Y.
PDGFR 是新型抗癌疗法的重要靶点，因为它在多种恶性肿瘤中过度表达。然而，最近一些抑制 PDGFR 信号传导的抗癌药物已与临床心力衰竭相关。了解 PDGFR 抑制剂的这种作用一直很困难，因为 PDGFR 信号传导在心脏中的作用在很大程度上仍未被探索。如本文所述，我们发现在暴露于负荷诱导的心脏应激的小鼠的心脏中PDGFR-β表达和激活显着增加。在发育中或成年期心脏中 Pdgfrb 被敲除的小鼠中，暴露于负荷引起的应激会导致心脏功能障碍和心力衰竭。从机制上讲，我们发现心肌细胞 PDGFR-β 信号在应激诱导的心脏血管生成中发挥着至关重要的作用。具体来说，我们证明心肌细胞 PDGFR-β 是心肌细胞应激诱导的旁分泌血管生成能力（血管生成潜力）的重要上游调节因子。这些结果表明，心肌细胞 PDGFR-β 是对压力超负荷引起的应激的代偿性心脏反应的调节剂。此外，我们的研究结果可能为抗癌 PDGFR 抑制剂引起的心脏毒性机制提供见解。
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.