Lavine Kory J, Kovacs Attila, Ornitz David M
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Clin Invest. 2008 Jul;118(7):2404-14. doi: 10.1172/JCI34561.
Hedgehog (HH) signaling has emerged as a critical pathway involved in the pathogenesis of a variety of tumors. As a result, HH antagonists are currently being evaluated as potential anticancer therapeutics. Conversely, activation of HH signaling in the adult heart may be beneficial, as HH agonists have been shown to increase coronary vessel density and improve coronary function after myocardial infarction. To investigate a potential homeostatic role for HH signaling in the adult heart, we ablated endogenous HH signaling in murine myocardial and perivascular smooth muscle cells. HH signaling was required for proangiogenic gene expression and maintenance of the adult coronary vasculature in mice. In the absence of HH signaling, loss of coronary blood vessels led to tissue hypoxia, cardiomyocyte cell death, heart failure, and subsequent lethality. We further showed that HH signaling specifically controlled the survival of small coronary arteries and capillaries. Together, these data demonstrate that HH signaling is essential for cardiac function at the level of the coronary vasculature and caution against the use of HH antagonists in patients with prior or ongoing heart disease.
刺猬信号通路（HH）已成为参与多种肿瘤发病机制的关键通路。因此，HH拮抗剂目前正在作为潜在的抗癌治疗药物进行评估。相反，成年心脏中HH信号通路的激活可能是有益的，因为HH激动剂已被证明可增加心肌梗死后的冠状动脉密度并改善冠状动脉功能。为了研究HH信号通路在成年心脏中的潜在稳态作用，我们在小鼠心肌和血管周围平滑肌细胞中消除了内源性HH信号。HH信号对于小鼠促血管生成基因表达和成年冠状动脉脉管系统的维持是必需的。在没有HH信号的情况下，冠状动脉血管的丧失导致组织缺氧、心肌细胞死亡、心力衰竭及随后的死亡。我们进一步表明，HH信号通路特异性地控制小冠状动脉和毛细血管的存活。总之，这些数据表明HH信号在冠状动脉脉管系统水平对心脏功能至关重要，并警示在患有既往或正在发作心脏病的患者中使用HH拮抗剂需谨慎。
