Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390-8573, USA.
Circ Res. 2011 Aug 5;109(4):407-17. doi: 10.1161/CIRCRESAHA.110.228452. Epub 2011 Jun 23.
Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling.
We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element.
Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility.
Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.
研究钙调神经磷酸酶在病理性心脏重构中的作用主要依赖于鼠模型，其中基因获得和缺失功能的操作在出生时或出生前就开始了。然而，绝大多数临床心脏病理学发生在成年人中。但是，当钙调神经磷酸酶在成年后开始激活时，其作用尚不清楚。此外，尽管心室肥厚是心力衰竭的一个公认的危险因素，但这两种主要的心脏疾病表型特征的进展速度和进展程度尚不清楚。最后，尽管成人的治疗干预旨在减缓、阻止或逆转疾病的发病机制，但对于钙调神经磷酸酶依赖性病理性重构的自发逆转能力知之甚少。
我们通过研究由四环素反应启动子元件驱动的组成型激活钙调神经磷酸酶转基因在心肌细胞中表达的小鼠，来解决这三个问题。
表达突变的钙调神经磷酸酶转基因的时间长短不同，以确定疾病发病机制的自然史，并确定这些事件是否具有可逆转性。成年小鼠中钙调神经磷酸酶转基因的激活引发了快速而强烈的心脏生长，具有病理性肥大的特征。收缩功能障碍、胎儿基因激活、纤维化和临床心力衰竭之前发生了向心性肥大。此外，当钙调神经磷酸酶活性被关闭时，心脏肥大会自发逆转，胎儿基因的表达也会恢复到基线水平。纤维化是病理性心脏重构的一个突出特征，表现出部分可逆性。
这些数据共同确立并定义了钙调神经磷酸酶信号在成年心脏中的有害作用，并揭示了钙调神经磷酸酶依赖性、向心性肥大先于收缩功能障碍和心力衰竭。此外，这些发现表明，在疾病过程的大部分时间里，钙调神经磷酸酶依赖性重构仍然是可逆的。
