Published online before print March 5, 2007, doi: 10.1161/HYPERTENSIONAHA.106.083568
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(Hypertension. 2007;49:1104.)
© 2007 American Heart Association, Inc.
Original Articles |
Disturbed Diurnal Rhythm Alters Gene Expression and Exacerbates Cardiovascular Disease With Rescue by Resynchronization
From the Toronto General Research Institute, Divisions of Cardiology and Cellular and Molecular Biology, University Health Network (T.A.M., N.T., P.L., N.K., P.P.L., F.D., M.J.S.); the Departments of Medicine or Physiology, Heart and Stroke, Richard Lewar Centre of Excellence (T.A.M., N.T., D.D.B., J.C., H.P., P.P.L., P.H.B., M.J.S.), and the Departments of Psychology and Zoology (M.R.R.), Centre for Biological Timing and Cognition, University of Toronto, Toronto, Ontario, Canada; and COBRA Biomathematical Research Applications (M.S.), Charlottesville, Va.
Correspondence to Michael J. Sole, 4N-488 Toronto General Hospital, 585 University Ave, Toronto, Ontario, Canada M5G 2N2. E-mail michael.sole{at}uhn.on.ca
Day/night rhythms are recognized as important to normal cardiovascular physiology and timing of adverse cardiovascular events; however, their significance in disease has not been determined. We demonstrate that day/night rhythms play a critical role in compensatory remodeling of cardiovascular tissue, and disruption exacerbates disease pathophysiology. We use a murine model of pressure overload cardiac hypertrophy (transverse aortic constriction) in a rhythm-disruptive 20-hour versus 24-hour environment. Echocardiography reveals increased left ventricular end-systolic and -diastolic dimensions and reduced contractility in rhythm-disturbed transverse aortic constriction animals. Furthermore, cardiomyocytes and vascular smooth muscle cells exhibit reduced hypertrophy, despite increased pressure load. Microarray and real-time PCR demonstrate altered gene cycling in transverse aortic constriction myocardium and hypothalamic suprachiasmatic nucleus. With rhythm disturbance, there is a consequent altered cellular clock mechanism (per2 and bmal), whereas key genes in hypertrophic pathways (ANF, BNP, ACE, and collagen) are downregulated paradoxical to the increased pressure. Phenotypic rescue, including reversal/attenuation of abnormal pathology and genes, only occurs when the external rhythm is allowed to correspond with the animals’ innate 24-hour internal rhythm. Our study establishes the importance of diurnal rhythm as a vital determinant in heart disease. Disrupted rhythms contribute to progression of organ dysfunction; restoration of normal diurnal schedules appears to be important for effective treatment of disease.
Key Words: cardiac hypertrophy • renin–angiotensin–aldosterone system pathway • remodeling • gene expression microarrays • circadian
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