title: Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease.
abstract: The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. ClockΔ19/Δ19mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness. Young ClockΔ19/Δ19hearts express dysregulated mRNAs and miRNAs in the PTEN-AKT signal pathways important for cardiac hypertrophy. We found a rhythm in the Pten gene and PTEN protein in WT hearts; rhythmic oscillations are lost in ClockΔ19/Δ19hearts. Changes in PTEN are associated with reduced AKT activation and changes in downstream mediators GSK-3β, PRAS40, and S6K1. Cardiomyocyte cultures confirm that Clock regulates the AKT signalling pathways crucial for cardiac hypertrophy. In old ClockΔ19/Δ19mice cardiac AKT, GSK3β, S6K1 phosphorylation are increased, consistent with the development of age-dependent cardiac hypertrophy. Lastly, we show that pharmacological modulation of the circadian mechanism with the REV-ERB agonist SR9009 reduces AKT activation and heart weight in old WT mice. Furthermore, SR9009 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction (TAC), supporting that the circadian mechanism plays an important role in regulating cardiac growth. These findings demonstrate a crucial role for Clock in growth and renewal; disrupting Clock leads to age-dependent cardiomyopathy. Pharmacological targeting of the circadian mechanism provides a new opportunity for treating heart disease.
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Faisal J
authors.initials: FJ
authors.lastname: Alibhai
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: LaMarre
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Cristine J
authors.initials: CJ
authors.lastname: Reitz
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Tsimakouridze
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kroetsch
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Shulman
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Steinberg
authors.affiliation: Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St Louis, MO, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.affiliation: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada. Electronic address: tmartino@uoguelph.ca.
authors.forename: Tami A
authors.initials: TA
authors.lastname: Martino
mesh_terms: D000375:Aging; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D057906:Circadian Clocks; D004195:Disease Models, Animal; D004452:Echocardiography; D005786:Gene Expression Regulation; D006439:Hemodynamics; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D056926:CLOCK Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: Aging; Cardiac hypertrophy; Cardiovascular; Circadian; MicroRNA