In vivo murine cardiac hypertrophy: A novel model to identify genetic signaling mechanisms that activate an adaptive physiological response
Background. The signaling mechanisms that activate and regulate various alterations in cardiac gene expression during in vivo myocardial hypertrophy are largely unknown. Methods and Results. A model of left ventricular hypertrophy in the intact mouse was developed by use of microsurgical techniques, and the degree and histological nature of the hypertrophy were characterized. The activation of immediate early genes and the atrial natriuretic factor (ANF) gene, well known to accompany hypertrophy, was also investigated. A stable 35-45 mm Hg pressure gradient was produced across the transverse thoracic aorta of the mouse, associated with rapid and transient expression of an immediate early gene program (c-fos/c-jun/jun B/Egr-1), an increase in ratio of heart weight to body weight, myocardial cell hypertrophy, and a 20-fold increase in endogenous ANF messenger RNA at 1 week. All of these responses are identical to those in cultured cell and other in vivo models of hypertrophy. It was further shown that Egr-1 can be induced within 15 minutes by α1-adrenergic receptor stimulation with phenylephrine infusion, as in cultured cells. Conclusions. This murine model demonstrates the feasibility of applying microsurgical techniques to study in vivo cardiac physiology in transgenic mice, and it should allow the application of genetic approaches to identify the mechanisms that activate gene expression in in vivo cardiac hypertrophy and in the transition from compensated hypertrophy to overt heart failure.
Rockman, HA; Knowlton, KU; Ross, J; Chien, KR
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