Published Online
on March 5, 2007

A more recent version of this article appeared on May 1, 2007

This Article Full Text (PDF) Data Supplement All Versions of this Article: 49/5/1104    most recent HYPERTENSIONAHA.106.083568v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martino, T. A. Articles by Sole, M. J. Search for Related Content PubMed PubMed Citation Articles by Martino, T. A. Articles by Sole, M. J. Pubmed/NCBI databases Medline Plus Health Information High Blood Pressure Related Collections Animal models of human disease Functional genomics Gene expression Gene regulation Hypertension - basic studies Hypertrophy

Submitted on October 26, 2006
Revised on November 13, 2006

Disturbed Diurnal Rhythm Alters Gene Expression and Exacerbates Cardiovascular Disease With Rescue by Resynchronization

Tami A. Martino; Nazneen Tata; Denise D. Belsham; Jennifer Chalmers; Marty Straume; Paul Lee; Horia Pribiag; Neelam Khaper; Peter P. Liu; Fayez Dawood; Peter H. Backx; Martin R. Ralph; and Michael J. Sole^*

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.

^* To whom correspondence should be addressed. E-mail: michael.sole{at}uhn.on.ca.

Abstract--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

This article has been cited by other articles:

				K. Hu, F. A.J.L. Scheer, R. M. Buijs, and S. A. Shea The circadian pacemaker generates similar circadian rhythms in the fractal structure of heart rate in humans and rats Cardiovasc Res, October 1, 2008; 80(1): 62 - 68. [Abstract] [Full Text] [PDF]

				J. A Chalmers, S.-Y. J Lin, T. A Martino, S. Arab, P. Liu, M. Husain, M. J Sole, and D. D Belsham Diurnal profiling of neuroendocrine genes in murine heart, and shift in proopiomelanocortin gene expression with pressure-overload cardiac hypertrophy J. Mol. Endocrinol., September 1, 2008; 41(3): 117 - 124. [Abstract] [Full Text] [PDF]

				Kun Hu, F. A. J. L. Scheer, R. M. Buijs, and S. A. Shea The Endogenous Circadian Pacemaker Imparts a Scale-Invariant Pattern of Heart Rate Fluctuations across Time Scales Spanning Minutes to 24 Hours J Biol Rhythms, June 1, 2008; 23(3): 265 - 273. [Abstract] [PDF]

				S. Y. Boateng and P. H. Goldspink Assembly and maintenance of the sarcomere night and day Cardiovasc Res, March 1, 2008; 77(4): 667 - 675. [Abstract] [Full Text] [PDF]

				T. A. Martino, N. Tata, G. A. Bjarnason, M. Straume, and M. J. Sole Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for translational medicine and body time of day Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1430 - R1437. [Abstract] [Full Text] [PDF]

				U. Albrecht, A. Bordon, I. Schmutz, and J. Ripperger The Multiple Facets of Per2 Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 95 - 104. [Abstract] [PDF]