Abstract 15458: Cardiomyocyte-Specific Disruption of the Circadian Clock Gene, Bmal1, Alters Cardiomyocyte Stiffness and Gives Rise to a Transient Cardiac Hypertrophy
Circadian rhythms are oscillations in behavior and physiology with a periodicity of approximately 24 hours. Disruption of circadian rhythms, in both humans and animal models, is correlated with an increased incidence of cardiovascular disease. Our lab has observed that mice lacking the core circadian clock gene, Bmal1-/-, develop dilated cardiomyopathy (DCM) at 8 weeks of age, with progressive deterioration of cardiac function until their time of death, demonstrating that Bmal1 is critical for maintenance of cardiac function. In addition, we observed disruption in sarcomere architecture and sarcomeric titin isoform composition, suggesting that changes in titin and cardiomyocyte stiffness are possible mediators of the pathologies seen in the hearts of Bmal1 deficient mice. To evaluate the role of the cardiomyoctye molecular clock on cardiac function, we created a conditional tamoxifen-induced cardiac-specific Bmal1-/- mouse strain, with the hypothesis that loss of Bmal1 specifically in cardiomyocytes is sufficient for disrupted cardiomyocyte mechanical function and progression to DCM. We found that the conditional cardiac-specific Bmal1-/- mice develop a transient cardiac hypertrophy two weeks post Bmal1 deletion as assessed by echocardiography (n =10, p<0.01) and heart to body weight ratio (n =13, p <0.001). This was accompanied by a decrease in cardiomyocyte stiffness as assessed by single cardiomyocyte passive tension analysis (n=20 cells, p<0.001). This hypertrophy is not due to tamoxifen or Cre toxicity, as the appropriate controls (MHCaCRE+/- and MHCaCRE-/-Bmal1flox/flox mice) did not become hypertrophic two weeks after treatment with tamoxifen. The cardiac-specific Bmal1-/- hearts begin to hypertrophy again at around 16 weeks of age and remain hypertrophic up to 36 weeks post Bmal1 excision, associated with an increase in pulse pressure (n=6, p<0.05). Together, these results suggest that the lack of an intact molecular clock or of Bmal1 in the heart is sufficient to induce changes in cardiomyocyte stiffness and lead to a transient significant hypertrophy of the myocardium. These mice are currently being followed to determine if their cardiac hypertrophy is compensatory with eventual progression to dilation and failure.
- © 2011 by American Heart Association, Inc.