Abstract 084: Dkk1 Knock out Leads To Augmentation Of Cardiac Hypertrophy Following Aortic Banding
Background: Myocardial hypertrophy is an important risk factor for cardiac morbidity and mortality. In the normal adult heart, Wnt signaling remains quiescent. However, recent studies have demonstrated reactivation of Wnt signaling in hypertrophic growth of cardiomyocytes. Under such conditions Wnt signaling may be beneficial or maladaptive depending on the context. The Wnt coreceptors LRP5 and LRP6 are important for signal transmission via the β-catenin pathway and are negatively regulated by Dkk1, a member of a small family of secretory proteins. Dkk1 binds to LRP6 and thereby acts as a Wnt antagonist. In our study we investigated the cardiovascular phenotype of Dkk1 knock-out mice following aortic banding.
Study Design and Results: Dkk1 (+/-) knock-out mice were subjected to aortic banding (AB) or sham operation. After 4 weeks echocardiographic and invasive measurements were performed. After that the mice were euthanized, heart weight was measured and myocardial samples were snap frozen for biochemical measurements or fixed in formalin for further histological evaluation. Under baseline conditions there were no differences in cardiomyocyte size, heart weight and cardiac function in Dkk1 knock-out animals compared to wild type animals. 4 weeks after aortic banding we observed a significant increase in heart weight/body weight ratio in Dkk1 knock out animals compared to the control group (7.3 ± 0.3 mg/g vs. 6.4 ± 0.3 mg/g, p < 0.05). Furthermore cardiomyocyte size was highly elevated in Dkk1 knock out mice compared to control animals, suggesting an augmentation in cardiac hypertrophy. Transcription levels of the pro-hypertrophic markers atrial natriuretic factor (ANF) and beta-MHC were increased in Dkk1 knock out animals. Interestingly echocardiographic data revealed an aggravation of cardiac function in Dkk1 knock out mice following aortic banding (Ejection fraction (EF): 62 ± 3 % vs. 74 ± 1 %, p < 0.05).
Summary: Our findings suggest that Dkk1 knock out aggravates cardiac hypertrophy following aortic banding. The underlying molecular mechanisms remain to be further explored.
- © 2013 by American Heart Association, Inc.