Abstract 15588: The Cardiomyocyte Circadian Clock Modulates Responsiveness of the Heart to Hypertrophic Stimuli
Introduction: Non-dipping hypertensive patients (i.e., blood pressure drops <10% during sleep) exhibit increased left ventricular hypertrophy and greater risk for cardiovascular and renal disease (compared to dipping hypertensive subjects). Similarly, obstructive sleep apnea is associated with increased sympathetic stimulation on the heart during the sleep phase, adverse cardiac remodeling and increased risk of heart failure. The cardiomyocyte circadian clock has recently been shown to modulate responsiveness of the heart to both physiological and pathological stimuli over the course of the day.
Hypothesis: The heart exhibits time-of-day-dependent oscillations in responsiveness to hypertrophic stimuli, which is mediated by the cardiomyocyte circadian clock.
Methods/Results: Wild-type mice exhibit 1.7-fold greater cardiac hypertrophic growth (and 8.1-fold greater anf mRNA induction) when challenged with the hypertrophic agonist isoproterenol (5mg/Kg/day, for 1-wk) at the active-to-sleep phase transition versus the sleep-to-active phase transition (p<0.05). Consistent with greater responsiveness to hypertrophic stimuli at the active-to-sleep phase transition, wild-type hearts exhibit increased P-AKT, P-GSK3β, and mcip1 mRNA at this time (p<0.05). These three parameters are chronically elevated in hearts isolated from a murine model in which the cardiomyocyte circadian clock is temporally suspended at the active-to-sleep transition; termed CCM mice (p<0.05). CCM mice display cardiac hypertrophy and anf induction (21% and 32%, respectively; p<0.05) relative to wild-type littermates. Importantly, CCM mice exhibit augmented cardiac hypertrophy (and anf induction) in response to diet-induced obesity (11% and 22% increases in heart weight following 16-wks high fat feeding, for wild-type and CCM mice, respectively; p<0.05) and transverse aortic constriction (21% and 38% increases in heart weight following 6-wks pressure overload, for wild-type and CCM mice, respectively; p<0.05).
Conclusions: Thus, the cardiomyocyte circadian clock plays a key role in regulating pathological cardiac hypertrophy, by increasing responsiveness of the myocardium to hypertrophic stimuli at the active-to-sleep phase transition.
- © 2010 by American Heart Association, Inc.