Main content

The Cardiac Circadian Proteome and Transcriptome: a Novel Paradigm Characterizing Cardiovascular Health and Disease

Show simple item record

dc.contributor.advisor Martino, Tami
dc.contributor.author Podobed, Petr
dc.date.accessioned 2014-08-25T19:30:51Z
dc.date.available 2014-08-25T19:30:51Z
dc.date.copyright 2014-08
dc.date.created 2014-08-19
dc.date.issued 2014-08-25
dc.identifier.uri http://hdl.handle.net/10214/8333
dc.description.abstract Circadian rhythms in cardiovascular physiological and molecular processes are essential for cardiac health in the diurnal (day/night) environment. The circadian clock mechanism found in most peripheral tissues, including the heart, controls circadian rhythms by regulating ~24h cycles in gene expression. Previous studies have shown that 9-13% of cardiac genes exhibit circadian rhythms in mRNA levels. However, these studies are insufficient, because proteins, and not mRNA, carry out most biological processes in the cell. This thesis investigated diurnal cardiac proteome in health and disease and the mechanisms underlying protein abundance rhythms. The first study introduced a cardiovascular circadian proteomics field of investigation and described the application of two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry for detecting temporal changes in protein abundance in healthy and diseased mouse hearts. The second study quantified the healthy murine cardiac proteome across a 12:12 light/dark (LD) cycle by 2D-DIGE and revealed that 90 out of 1147 (~8%) spots exhibited significant rhythmic changes in abundance. Half of the identified diurnal proteins had statistically significant changes in expression of their corresponding mRNA. Alterations in cardiac proteome were detected in cardiomyocyte specific clock mutant (CCM) mice, consistent with the regulation by the clock mechanism. Diurnal disruption (10:10 LD) altered rhythmic protein expression, and cardiac contractility on the Langendorff apparatus. Diurnal proteome could also be important in heart disease, as 70 out of 998 (7%) of detected cardiac proteins and peripheral blood cytokines exhibited diurnal changes in abundance in a murine model of cardiac hypertrophy induced by transverse aortic constriction (TAC). Diurnal rhythms in myofilament ATP consumption were reduced in TAC hearts compared to controls. The third study developed a bioinformatics framework to investigate clock-controlled transcription in the heart. Putative clock-controlled genes exhibited a characteristic circadian expression pattern and had conserved E-box cis enhancer elements in their promoters. The bioinformatics approach was experimentally validated by demonstrating that the circadian clock regulated rhythmic expression of the titin cap gene. Collectively, this thesis supports a novel paradigm in cardiovascular biology: temporal gene and protein expression is an important factor affecting cardiovascular health and disease. en_US
dc.description.sponsorship Ontario Veterinary College; Heart and Stroke Foundation of Canada; Canadian Institutes of Health Research en_US
dc.language.iso en en_US
dc.rights Attribution-NonCommercial-NoDerivs 2.5 Canada *
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/2.5/ca/ *
dc.subject heart en_US
dc.subject heart disease en_US
dc.subject cardiovascular en_US
dc.subject tac en_US
dc.subject pressure overload en_US
dc.subject transverse aortic constriction en_US
dc.subject left ventricule en_US
dc.subject circadian en_US
dc.subject diurnal en_US
dc.subject clock en_US
dc.subject light dark en_US
dc.subject bmal1 en_US
dc.subject tcap en_US
dc.subject titin cap en_US
dc.subject telethonin en_US
dc.subject proteomics en_US
dc.subject 2D-DIGE en_US
dc.subject DIGE en_US
dc.subject mass spectrometry en_US
dc.title The Cardiac Circadian Proteome and Transcriptome: a Novel Paradigm Characterizing Cardiovascular Health and Disease en_US
dc.type Thesis en_US
dc.degree.programme Biomedical Sciences en_US
dc.degree.name Doctor of Philosophy en_US
dc.degree.department Department of Biomedical Sciences en_US
dc.rights.license All items in the Atrium are protected by copyright with all rights reserved unless otherwise indicated.


Files in this item

Files Size Format View Description
Podobed_Petr_201408_PhD.pdf 6.608Mb PDF View/Open Thesis Podobed

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivs 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 2.5 Canada