De Windt L J, Lim H W, Bueno O F, Liang Q, Delling U, Braz J C, Glascock B J, Kimball T F, del Monte F, Hajjar R J, Molkentin J D
Divisions of Molecular Cardiovascular Biology and Cardiology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3322-7. doi: 10.1073/pnas.031371998.
The Ca(2+)-calmodulin-activated Ser/Thr protein phosphatase calcineurin and the downstream transcriptional effectors of calcineurin, nuclear factor of activated T cells, have been implicated in the hypertrophic response of the myocardium. Recently, the calcineurin inhibitory agents cyclosporine A and FK506 have been extensively used to evaluate the importance of this signaling pathway in rodent models of cardiac hypertrophy. However, pharmacologic approaches have rendered equivocal results necessitating more specific or genetic-based inhibitory strategies. In this regard, we have generated Tg mice expressing the calcineurin inhibitory domains of Cain/Cabin-1 and A-kinase anchoring protein 79 specifically in the heart. DeltaCain and DeltaA-kinase-anchoring protein Tg mice demonstrated reduced cardiac calcineurin activity and reduced hypertrophy in response to catecholamine infusion or pressure overload. In a second approach, adenoviral-mediated gene transfer of DeltaCain was performed in the adult rat myocardium to evaluate the effectiveness of an acute intervention and any potential species dependency. DeltaCain adenoviral gene transfer inhibited cardiac calcineurin activity and reduced hypertrophy in response to pressure overload without reducing aortic pressure. These results provide genetic evidence implicating calcineurin as an important mediator of the cardiac hypertrophic response in vivo.
钙离子/钙调蛋白依赖性丝氨酸/苏氨酸蛋白磷酸酶钙调神经磷酸酶以及钙调神经磷酸酶的下游转录效应物——活化T细胞核因子，与心肌肥大反应有关。最近，钙调神经磷酸酶抑制剂环孢素A和FK506已被广泛用于评估该信号通路在啮齿动物心脏肥大模型中的重要性。然而，药理学方法得出的结果并不明确，因此需要更具特异性或基于基因的抑制策略。在这方面，我们构建了在心脏中特异性表达Cain/Cabin-1和A激酶锚定蛋白79的钙调神经磷酸酶抑制结构域的转基因小鼠。DeltaCain和DeltaA激酶锚定蛋白转基因小鼠表现出心脏钙调神经磷酸酶活性降低，并且对儿茶酚胺输注或压力超负荷的肥大反应减弱。在第二种方法中，在成年大鼠心肌中进行了腺病毒介导的DeltaCain基因转移，以评估急性干预的有效性以及任何潜在的物种依赖性。DeltaCain腺病毒基因转移抑制了心脏钙调神经磷酸酶活性，并减轻了对压力超负荷的肥大反应，而不会降低主动脉压力。这些结果提供了遗传学证据，表明钙调神经磷酸酶是体内心脏肥大反应的重要介质。
