Published Online
on March 9, 2009

A more recent version of this article appeared on March 24, 2009

This Article Full Text (PDF) Data Supplement All Versions of this Article: 119/11/1510    most recent CIRCULATIONAHA.108.827477v1 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 Anea, C. B. Articles by Rudic, R. D. Search for Related Content PubMed PubMed Citation Articles by Anea, C. B. Articles by Rudic, R. D. Related Collections Remodeling Animal models of human disease Genetically altered mice Peripheral vascular disease Arterial thrombosis Endothelium/vascular type/nitric oxide Related Article

Submitted on October 10, 2008
Accepted on December 30, 2008

Vascular Disease in Mice With A Dysfunctional Circadian Clock

Ciprian B. Anea MD, Maoxiang Zhang PhD, David W. Stepp PhD, G. Bryan Simkins BS, Guy Reed MD, David J. Fulton PhD, and R. Daniel Rudic PhD^*

From the Department of Pharmacology and Toxicology (C.B.A., M.Z., G.B.S., D.J.F., R.D.R.), Department of Physiology (D.W.S.), Vascular Biology Center (D.W.S., D.J.F.), and Cardiology Division, Department of Medicine (G.R.), Medical College of Georgia, Augusta.

^* To whom correspondence should be addressed. E-mail: rrudic{at}mcg.edu.

Background—Cardiovascular disease is the leading cause of death for both men and women in the United States and the world. A profound pattern exists in the time of day at which the death occurs; it is in the morning, when the endothelium is most vulnerable and blood pressure surges, that stroke and heart attack most frequently happen. Although the molecular components of circadian rhythms rhythmically oscillate in blood vessels, evidence of a direct function for the "circadian clock" in the progression to vascular disease is lacking.

Methods and Results—In the present study, we found increased pathological remodeling and vascular injury in mice with aberrant circadian rhythms, Bmal1-knockout and Clock mutant. In addition, naive aortas from Bmal1-knockout and Clock mutant mice exhibit endothelial dysfunction. Akt and subsequent nitric oxide signaling, a pathway critical to vascular function, was significantly attenuated in arteries from Bmal1-knockout mice.

Conclusions—Our data reveal a new role for the circadian clock during chronic vascular responses that may be of significance in the progression of vascular disease.

Key words: circadian rhythm • endothelium • remodeling • thrombus • vasculature

Related Article:

Clinical Summaries
Circulation 2009 119: 1457-1458. [Extract] [Full Text]

This article has been cited by other articles:

				T. A. Martino and M. J. Sole Molecular Time: An Often Overlooked Dimension to Cardiovascular Disease Circ. Res., November 20, 2009; 105(11): 1047 - 1061. [Abstract] [Full Text] [PDF]

				R. D. Rudic Time Is of the Essence: Vascular Implications of the Circadian Clock Circulation, October 27, 2009; 120(17): 1714 - 1721. [Full Text] [PDF]

				M. J. Sole and T. A. Martino Diurnal physiology: core principles with application to the pathogenesis, diagnosis, prevention, and treatment of myocardial hypertrophy and failure J Appl Physiol, October 1, 2009; 107(4): 1318 - 1327. [Abstract] [Full Text] [PDF]

				R. D. Rudic and D. J. Fulton Pressed for time: the circadian clock and hypertension J Appl Physiol, October 1, 2009; 107(4): 1328 - 1338. [Abstract] [Full Text] [PDF]

				J. F. Keaney Jr and D. R. Weaver Vascular Rhythms and Adaptation: Do Your Arteries Know What Time It Is? Circulation, March 24, 2009; 119(11): 1463 - 1466. [Full Text] [PDF]