Location of Repository

Molecular biology of the circadian clock in the rodent heart

By Joanne Helen Singletary

Abstract

Circadian rhythms are physiological and behavioural patterns with a period of approximately 24 hours that allow almost all organisms to anticipate predictable changes in their environment. In mammals, these rhythms are co-ordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei (SCN) that is synchronised to solar time by retinal signals. Rhythms are generated at the cellular level by interlocking auto-regulatory transcriptional/post-translational feedback loops known as the circadian clock. The same mechanism exists in all mammalian cells investigated, including components of the cardiovascular system (CVS). Signals from the clock are translated into physiological rhythms via the regulation of clock-controlled genes (CCGs) and recent observations suggest that over 10% of the transcriptome is rhythmically expressed. Disruption of the clock is associated with chronic illness such as cardiovascular disease, cancer and diabetes and in the human CVS circadian rhythms in cardiac function and the occurrence of pathological events have been observed. The molecular targets of the clock in the heart are however largely unconfirmed.\ud The aim of this thesis was to identify CCGs in the mouse heart and investigate their regulation by the clock using in vivo and in vitro approaches. SCN-dependent temporal expression and up-regulation by clock factors suggests for the first time that Bnp is a cardiac CCG and, with the putative CCGs Anp and Ms1, implicates the cardiac clock in regulating hypertrophy, and cardio-protection. Treatment of SCN-ablated mice with dexamethasone re-established circadian expression of Bnp and altered expression of most genes investigated, implicating glucocorticoids in synchronisation of the cardiac clock and target processes. Cardiac circadian expression of Pai-1 was confirmed and direct transcriptional regulation by the clock was demonstrated. A novel E-box-containing distal region in the Pai-1 promoter was identified which may be sufficient to generate cycling in dexamethasone-synchronised cells.\ud E-box dependent activation of this distal region and the proximal promoter by clock and hypoxic factors suggests the E-box provides the molecular interface between circadian and stress pathways and that Pai-1 is a key integrator of the circadian clockwork and diverse physiological processes in the CVS.\ud Together these and previous findings suggest the cardiac clock can control complex co-ordination of gene cascades and integrate diverse processes with adaptation to the temporal environment, providing a molecular explanation for the diurnal variation in cardiovascular events and suggesting new therapeutic targets

Publisher: University of Leicester
Year: 2009
OAI identifier: oai:lra.le.ac.uk:2381/8197

Suggested articles

Preview

Citations

  1. (2003). A clockwork web: circadian timing in brain and periphery, in health and disease.
  2. (2006). A constitutively active hypoxia-inducible factor-1alpha/VP16 hybrid factor activates expression of the human B-type natriuretic peptide gene.
  3. (1996). A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms.
  4. A direct repeat of E-box-like elements is required for cell-autonomous circadian rhythm of clock genes.
  5. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.
  6. (1996). A light-entrainment mechanism for the Drosophila circadian clock.
  7. A longitudinal study on the relationship between shift work and the progression of hypertension in male Japanese workers.
  8. (1999). A Na+-activated K+ current (IK,Na) is present in guinea-pig but not rat ventricular myocytes.
  9. (2001). A new mathematical model for relative quantification in real-time RT-PCR.
  10. (2005). A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo. PNAS
  11. (2005). A role for glycogen synthase kinase-3beta in the mammalian circadian clock.
  12. (1998). A serum shock induces circadian gene expression in mammalian tissue culture cells.
  13. (2002). a striated muscle activator of Rho signaling and serum response factor-dependent transcription.
  14. (2002). A transcription factor response element for gene expression during circadian night.
  15. (1985). A uniform enzymatic method for dissociation of myocytes from hearts and stomachs of vertebrates.
  16. (2005). A.J.: Determinants of inducible brain natriuretic peptide promoter activity.
  17. (2006). Abnormal blood pressure circadian rhythm: a target organ damage?
  18. (2000). Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays.
  19. (2007). Activation of p38/MEF2C pathway by alltrans retinoic acid in cardiac myoblasts.
  20. (2004). Acute myocardial hypoxia increases BNP gene expression.
  21. (2005). Acute physical stress elevates mouse period1 mRNA expression in mouse peripheral tissues via a glucocorticoid-responsive element.
  22. (2003). Adrenergic regulation of clock gene expression in mouse liver.
  23. (2000). Age-dependent changes of the circadian system.
  24. (2005). Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes.
  25. (2007). Aldosterone induces circadian gene expression of clock genes in H9c2 cardiomyoblasts.
  26. (1995). Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction.
  27. (2002). Alterations of the circadian clock in the heart by streptozotocin-induced diabetes.
  28. (2002). Alternative splicing yields novel BMAL2 variants: tissue distribution and functional characterization.
  29. (2000). an essential pacemaker component, controls expression of the circadian transcription factor DBP.
  30. (2001). An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.
  31. (2006). An opposite role for tau in circadian rhythms revealed by mathematical modeling.
  32. (1991). and electrophysiological characterization of a clonal cell (H9c2) line from rat heart.
  33. (2001). Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism.
  34. (2003). Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: importance of cyclic GMP.
  35. (2003). Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia.
  36. (1996). Apoptosis in ischemic and reperfused rat myocardium.
  37. (2006). ARC protects rat cardiomyocytes against oxidative stress through inhibition of caspase-2 mediated mitochondrial pathway.
  38. (1998). ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases.
  39. (1994). Archaic structure of the gene encoding transcription factor USF.
  40. (1997). Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men.
  41. (2007). Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes.
  42. (2004). Atrial natriuretic peptide dose-dependently inhibits pressure overload-induced cardiac remodeling.
  43. (2004). B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation.
  44. (2004). Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression.
  45. (2004). BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis.
  46. (2008). cAMP-dependent signaling as a core component of the mammalian circadian pacemaker.
  47. (1997). Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses.
  48. (2005). Cardiac gene expression profile in rats with terminal heart failure and cachexia.
  49. (1999). Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart.
  50. (2000). Cardiovascular Basic Helix Loop Helix Factor 1, a Novel Transcriptional Repressor Expressed Preferentially in the Developing and Adult Cardiovascular System.
  51. (2002). cDNA array analysis of pineal gene expression reveals circadian rhythmicity of the dominant negative helix-loop-helix protein-encoding gene,
  52. (1997). cDNA cloning and tissue-specific expression of a novel basic helix-loophelix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage.
  53. (2006). Cell type-dependent regulation of the hypoxia-responsive plasminogen activator inhibitor-1 gene by upstream stimulatory factor-2.
  54. (1998). Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.
  55. (1997). Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway.
  56. (1996). Chronopharmacology of hypertension.
  57. (2007). Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation.
  58. (2000). Circadian and glucocorticoid regulation of Rev-erbalpha expression in liver.
  59. (2004). Circadian and lightinduced transcription of clock gene Per1 depends on histone acetylation and deacetylation.
  60. (2001). Circadian chronotherapy for human cancers.
  61. (2005). Circadian clock control by SUMOylation of BMAL1.
  62. (2008). Circadian clock function in Arabidopsis thaliana: time beyond transcription.
  63. (2006). Circadian clock genes cause activation of the human PAI-1 gene promoter with 4G/5G allelic preference.
  64. (2006). Circadian clock molecules CLOCK and CRYs modulate fibrinolytic activity by regulating the PAI1 gene expression.
  65. (2006). Circadian clocks are resounding in peripheral tissues.
  66. (2007). Circadian clocks: regulators of endocrine and metabolic rhythms.
  67. (2007). Circadian clocks: timely interference by microRNAs.
  68. (2002). Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus.
  69. (2003). Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons.
  70. (2005). Circadian expression of clock genes and clock-controlled genes in the rat retina.
  71. (1999). Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP.
  72. (2005). Circadian gene expression in cultured cells.
  73. (2004). Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells.
  74. (2007). Circadian genes, rhythms and the biology of mood disorders.
  75. (2006). Circadian orchestration of the hepatic proteome.
  76. (2007). Circadian profiling of the transcriptome in NIH/3T3 fibroblasts: comparison with rhythmic gene expression in SCN2.2 cells and the rat SCN.
  77. (2002). Circadian Programs of Transcriptional Activation, Signaling, and Protein Turnover Revealed by Microarray Analysis of Mammalian Cells.
  78. (2001). Circadian regulation of diverse gene products revealed by mRNA expression profiling of synchronized fibroblasts.
  79. (2006). Circadian regulator CLOCK is a histone acetyltransferase.
  80. (2006). Circadian rhythm generation in a glioma cell line.
  81. (2005). Circadian rhythms from multiple oscillators: lessons from diverse organisms.
  82. (2002). Circadian rhythms in drinking behavior and locomotor activity of rats
  83. (2007). Circadian rhythms in the CNS and peripheral clock disorders: human sleep disorders and clock genes.
  84. (1985). Circadian rhythms of epinephrine and norepinephrine in man.
  85. (1997). Circadian rhythms: basic neurobiology and clinical applications.
  86. (2002). Circadian Transcription. Thinking outside the E-Box.
  87. (2002). Circadian variability in hemorrhagic stroke.
  88. (1989). Circadian variation and triggers of onset of acute cardiovascular disease.
  89. (1991). Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity.
  90. (2007). Circadian variation of blood pressure and the vascular response to asynchronous stress.
  91. (1978). Circadian variation of blood-pressure.
  92. (2003). Circadian variation of cardiac K+ channel gene expression.
  93. (2000). CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression.
  94. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock.
  95. (2002). Clock genes in mammalian peripheral tissues.
  96. Clock genes in the heart: characterization and attenuation with hypertrophy.
  97. (2004). Clock genes, oscillators, and cellular networks in the suprachiasmatic nuclei.
  98. CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor alpha (PPARalpha) in mice.
  99. (1971). Clock mutants of Drosophila melanogaster.
  100. (2007). CLOCK-mediated acetylation of BMAL1 controls circadian function.
  101. (2001). Cloning of mouse BMAL2 and its daily expression profile in the suprachiasmatic nucleus: a remarkable acceleration of Bmal2 sequence divergence after Bmal gene duplication.
  102. (2007). Clustal W and Clustal X version 2.0.
  103. (1999). components of the negative limb of the circadian clock feedback loop.
  104. (2004). Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.
  105. (2004). Connective tissue growth factor--a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats.
  106. (2000). Connective tissue growth factor: what's in a name?
  107. (2004). ConSite: web-based prediction of regulatory elements using cross-species comparison.
  108. (2005). Control of mammalian circadian rhythm by CKIepsilon-regulated proteasomemediated PER2 degradation.
  109. (1998). Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.
  110. (2002). Coordinated transcription of key pathways in the mouse by the circadian clock.
  111. (2002). Coordination of circadian timing in mammals.
  112. (2003). Cross-talk between hypoxic and circadian pathways: cooperative roles for hypoxia-inducible factor 1alpha and CLOCK in transcriptional activation of the vasopressin gene.
  113. (2000). CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis.
  114. (1992). Current concepts of pathophysiology, circadian patterns, and vasoreactive factors associated with myocardial ischemia detected by ambulatory electrocardiography.
  115. (2005). CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless.
  116. (2002). Daily expression of mRNAs for the mammalian Clock genes Per2 and clock in mouse suprachiasmatic nuclei and liver and human peripheral blood mononuclear cells.
  117. (1990). DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally.
  118. (2002). Dec1 and Dec2 are regulators of the mammalian molecular clock.
  119. (1989). Detection and Analysis of Proteins Expressed from Cloned Genes, Molecular Cloning: A Laboratory Manual.
  120. (1996). Dexamethasone and stress upregulate Kv1.5 K+ channel gene expression in rat ventricular myocytes.
  121. (2006). Dexamethasone could improve myocardial infarction outcomes and provide new therapeutic options for non-interventional patients.
  122. (2005). Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors.
  123. (2005). Differential control of peripheral circadian rhythms by suprachiasmatic-dependent neural signals.
  124. (2002). Differential induction and localization of mPer1 and mPer2 during advancing and delaying phase shifts.
  125. (2004). Differentiation of H9c2 cardiomyoblasts: The role of adenylate cyclase system.
  126. (1999). Direct comparison of GAPDH, beta-actin, cyclophilin, and 28S rRNA as internal standards for quantifying RNA levels under hypoxia.
  127. (2008). Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression.
  128. (2001). Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice.
  129. (2007). Disturbed diurnal rhythm alters gene expression and exacerbates cardiovascular disease with rescue by resynchronization.
  130. (2002). Diurnal variation in PAI-1 activity predominantly confined to the 4G-allele of the PAI-1 gene.
  131. (1989). Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1).
  132. (1984). Diurnal variations of plasma growth hormone, thyrotropin, thyroxine, and triiodothyronine in streptozotocin-diabetic and food-restricted rats.
  133. (2004). DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated transcription regulation of the circadian gene mPer1.
  134. (2003). DNA microarray analyses of circadian timing: the genomic basis of biological time.
  135. (2003). DNA microarray analysis of in vivo progression mechanism of heart failure.
  136. (1998). double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation.
  137. (2008). Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex.
  138. (2006). Dual role of the CLOCK/BMAL1 circadian complex in transcriptional regulation.
  139. (2007). E.: The metabolic consequences of sleep deprivation.
  140. (1993). E.R.: Ontogeny of corticosteroid receptors in the brain.
  141. (2004). ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes.
  142. (2005). Effect of streptozotocin-induced diabetes on daily expression of per2 and dbp in the heart and liver and melatonin rhythm in the pineal gland of Wistar rat.
  143. (2004). Effects of chronic jet lag on tumor progression in mice.
  144. (2002). Effects of gender and age on the levels and circadian
  145. (2007). Effects of rotating shift work on biomarkers of metabolic syndrome and inflammation.
  146. (1995). Effects of stress on Kv1.5 K+ channel gene expression in the left ventricle of rat hearts.
  147. (1999). Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters.
  148. (2002). Endothelial PAS domain protein 1 (EPAS1) induces adrenomedullin gene expression in cardiac myocytes: role of EPAS1 in an inflammatory response in cardiac myocytes.
  149. (1994). Energy metabolism of the heart: from basic concepts to clinical applications.
  150. (1998). Expression of Id1 Results in Apoptosis of Cardiac Myocytes through a Redox-dependent Mechanism.
  151. (1996). Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm.
  152. (1999). Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans.
  153. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels.
  154. (1986). Fibrinolytic system of cultured endothelial cells: regulation by plasminogen activator inhibitor.
  155. (2001). Fibrosis and ischemia: the real risks in hypertensive heart disease.
  156. (2000). Forskolin induces circadian gene expression of rPer1, rPer2 and dbp in mammalian rat-1 fibroblasts.
  157. (2005). Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.
  158. (1997). Functional identification of the mouse circadian Clock gene by transgenic BAC rescue.
  159. (1999). Functional promoter modules can be detected by formal models independent of overall nucleotide sequence similarity.
  160. (2000). GABA synchronizes clock cells within the suprachiasmatic circadian clock.
  161. (2002). Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy.
  162. (2007). Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium.
  163. (2003). Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters.
  164. (2008). Genetic components of the circadian clock regulate thrombogenesis in vivo.
  165. (1998). Genetic dissection of glucocorticoid receptor function in mice.
  166. Genome-wide expression analysis reveals 100 adrenal gland-dependent circadian genes in the mouse liver.
  167. (2004). Genome-wide expression profiling of a cardiac pressure overload model identifies major metabolic and signaling pathway responses.
  168. (2003). Genomewide expression analysis of mouse liver reveals CLOCK-regulated circadian output genes.
  169. (2001). Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators.
  170. (2007). Glucocorticoid signaling synchronizes the liver circadian transcriptome.
  171. (2007). Glucocorticoids and cardiovascular disease.
  172. (2002). Glucose downregulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts.
  173. (2004). Glucose transport in the heart.
  174. (1998). Glyceraldehyde-3-phosphate dehydrogenase is regulated on a daily basis by the circadian clock.
  175. (2003). Health disorders of shift workers.
  176. (2000). Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms.
  177. (1998). HIF-1 alpha is required for solid tumor formation and embryonic vascularization.
  178. (2002). Host circadian clock as a control point in tumor progression.
  179. (1999). Housekeeping genes as internal standards: use and limits.
  180. (2001). Human eHAND, but not dHAND, is down-regulated in cardiomyopathies.
  181. (1998). Humoral signals mediate the circadian expression of rat period homologue (rPer2) mRNA in peripheral tissues.
  182. (1997). Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci
  183. (2001). Hypothalamic integration of central and peripheral clocks.
  184. (2001). Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain.
  185. (2007). Hypoxia and circadian patterns.
  186. (2004). Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1.
  187. (2003). Id proteins in development, cell cycle and cancer.
  188. (2002). Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes.
  189. (2004). Identification of mPer1 phosphorylation sites responsible for the nuclear entry.
  190. (2002). Identification of Rev-erbalpha as a physiological repressor of apoC-III gene transcription.
  191. (2007). Identification of the circadian clock-regulated E-box element in the mouse plasminogen activator inhibitor-1 gene.
  192. (2007). Identification of the circadian transcriptome in adult mouse skeletal muscle.
  193. (2007). Impact of sleep and sleep loss on neuroendocrine and metabolic function.
  194. (1992). Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease.
  195. (2001). Impaired expression of the mPer2 circadian clock gene in the suprachiasmatic nuclei of aging mice.
  196. (2007). Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis.
  197. (2004). Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction.
  198. (1992). Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries.
  199. (1997). Inducibility of E4BP4 suggests a novel mechanism of negative gene regulation by glucocorticoids.
  200. (2001). Induction of basic helix-loop-helix protein DEC1 (BHLHB2)/Stra13/Sharp2 in response to the cyclic adenosine monophosphate pathway.
  201. (1993). Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation.
  202. (1999). Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes.
  203. (2000). Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders.
  204. (1996). Inhibitors of fibrinolysis are elevated in atherosclerotic plaque.
  205. Interaction with BMAL1.
  206. (2007). Intercellular coupling confers robustness against mutations in the SCN circadian clock network.
  207. (2000). Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure.
  208. Intrinsic diurnal variations in cardiac metabolism and contractile function.
  209. Involvement of circadian clock gene Clock in diabetes-induced circadian augmentation of plasminogen activator inhibitor-1 (PAI-1) expression in the mouse heart.
  210. (2000). Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock.
  211. (1973). Isolation of circadian clock mutants of Neurospora crassa.
  212. (2007). Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia.
  213. (2002). Large-scale analysis of the human and mouse transcriptomes.
  214. (1999). Light and diurnal cycle affect human heart rate: possible role for the circadian pacemaker.
  215. (2004). Light-induced phase-shifting of the peripheral circadian oscillator in the hearts of food-deprived mice.
  216. (1993). Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries.
  217. (1972). Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat.
  218. (1994). Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless.
  219. (1993). Mechanism of glucocorticoid induction of the rat plasminogen activator inhibitor-1 gene in HTC rat hepatoma cells: identification of cis-acting regulatory elements.
  220. (2007). Melatonin affects nuclear orphan receptors mRNA in the rat suprachiasmatic nuclei.
  221. (2006). Melatonin attenuates diabetesinduced oxidative stress in rabbits.
  222. (2006). Melatonin in the multi-oscillatory mammalian circadian world.
  223. (2006). Melatonin reduces night blood pressure in patients with nocturnal hypertension.
  224. (2005). Melatonin-induced modulation of glucose metabolism in primary cultures of rabbit kidney-cortex tubules.
  225. (1997). Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death.
  226. (2007). microRNA modulation of circadian-clock period and entrainment.
  227. (2007). Minireview: The circadian clockwork of the suprachiasmatic nuclei--analysis of a cellular oscillator that drives endocrine rhythms.
  228. (2002). Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1.
  229. modulates the circadian phase of clock gene expression.
  230. (2007). Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity.
  231. (2001). Molecular analysis of mammalian circadian rhythms.
  232. (1984). Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms.
  233. (1999). Molecular bases for circadian clocks.
  234. (1997). Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system.
  235. (2007). Molecular circadian rhythms in central and peripheral clocks in mammals.
  236. (2000). Molecular clock genes in man and lower animals: possible implications for circadian abnormalities in depression.
  237. (2001). Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins.
  238. (2006). Molecular components of the mammalian circadian clock.
  239. (2006). Molecular mechanism of cell-autonomous circadian gene expression of Period2, a crucial regulator of the mammalian circadian clock.
  240. (2001). Molecular mechanisms of the biological clock in cultured fibroblasts.
  241. (2005). Molecular regulation of the brain natriuretic peptide gene.
  242. (2002). ms1, a novel stressresponsive, muscle-specific gene that is up-regulated in the early stages of pressure overload-induced left ventricular hypertrophy.
  243. (1993). Multiple comparison procedures.
  244. (1995). Multiple Hypothesis Testing.
  245. (2003). Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice.
  246. Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts.
  247. (1998). Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain.
  248. (1994). Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior.
  249. (2005). Myocardial ischemia and reperfusion injury.
  250. (2003). Natriuretic peptides: markers or modulators of cardiac hypertrophy?
  251. (2006). Night work and risk of breast cancer.
  252. (2003). Night-shift work and risk of colorectal cancer in the nurses' health study.
  253. (2006). Nondippers are associated with adverse cardiac remodeling and dysfunction (R1).
  254. (2001). NPAS2: an analog of clock operative in the mammalian forebrain.
  255. (2000). Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon.
  256. (2007). Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart.
  257. (2005). Obesity and metabolic syndrome in circadian Clock mutant mice.
  258. (1990). Occurrence of oxidative stress during reperfusion of the human heart.
  259. (1999). Orphan nuclear hormone receptor RevErbalpha modulates expression from the promoter of the hydratase-dehydrogenase gene by inhibiting peroxisome proliferator-activated receptor alpha-dependent transactivation.
  260. (1997). Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix-loop-helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells.
  261. (2004). Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression.
  262. (2004). Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations.
  263. (1984). P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster.
  264. (2005). PAI-1 and atherothrombosis.
  265. (2007). PEDB : Mammalian Promoter/Enhancer DataBase (http://promoter.cdb.riken.jp/),
  266. (2003). Peripheral circadian oscillators in mammals: Time and food.
  267. Peripheral circadian oscillators require CLOCK.
  268. (1995). Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more.
  269. (2002). Peroxisome proliferator-activated receptors: lipid binding proteins controling gene expression.
  270. (2004). Phenylephrine and endothelin-1 upregulate connective tissue growth factor in neonatal rat cardiac myocytes.
  271. (2002). Photic and circadian expression of luciferase in mPeriod1-luc transgenic mice invivo.
  272. (2001). Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats.
  273. (1988). Plasma corticosterone, motor activity and metabolic circadian patterns in streptozotocin-induced diabetic rats.
  274. (2005). Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels.
  275. (2002). Plasminogen activator inhibitor 1 expression is regulated by the inflammatory mediators interleukin-1alpha, tumor necrosis factor-alpha, transforming growth factor-beta and oncostatin M in human cardiac myocytes.
  276. (2002). Plasminogen activator inhibitor 1: physiological and pathophysiological roles.
  277. (1999). Plasminogen activator inhibitor type-1 (PAI1) and its role in cardiovascular disease.
  278. (2001). Plasminogen activator inhibitor type-1 in cardiovascular disease. Status report
  279. (1995). Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes.
  280. (1994). Plasminogen activator inhibitor-1 expression in human liver and healthy or atherosclerotic vessel walls.
  281. (1997). Plasminogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography.
  282. (2005). Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease.
  283. (1990). Plasminogen activator inhibitors: hormonally regulated serpins.
  284. (2000). Plasminogen-activator inhibitor type 1 and coronary artery disease.
  285. (2005). Pleiotropic functions of plasminogen activator inhibitor-1.
  286. (1997). Positional cloning of the mouse circadian clock gene.
  287. (2000). Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau.
  288. (2004). Posttranscriptional and posttranslational regulation of clock genes.
  289. (2007). Posttranscriptional regulation of mammalian circadian clock output.
  290. (2001). Posttranslational mechanisms regulate the mammalian circadian clock.
  291. (2007). Potential role for peripheral circadian clock dyssynchrony in the pathogenesis of cardiovascular dysfunction.
  292. (2003). Potential roles of ROR-alpha in cardiovascular endocrinology.
  293. (2008). PPAR delta as a therapeutic target in metabolic disease.
  294. (2002). Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal cardiomyocytes.
  295. (1976). Properties of a clonal muscle cell line from rat heart.
  296. (2007). Putting numbers on the network connections.
  297. (2007). Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion.
  298. (2004). Rapid upregulation of CTGF in cardiac myocytes by hypertrophic stimuli: implication for cardiac fibrosis and hypertrophy.
  299. (2006). Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.
  300. (2002). Reduction of I(to) causes hypertrophy in neonatal rat ventricular myocytes.
  301. (1999). Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1. Annals of the New York Academy of Sciences 874
  302. (2001). Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock.
  303. (2001). Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.
  304. (1972). Regulation of glucocorticoid release.
  305. (1991). Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factoralpha, and transforming growth factor-beta.
  306. (2002). Regulatory modules shared within gene classes as well as across gene classes can be detected by the same in silico approach.
  307. (2004). Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells.
  308. Resetting of circadian time in peripheral tissues by glucocorticoid signaling.
  309. (1984). Restoration of circadian behavioural rhythms by gene transfer in Drosophila.
  310. (2001). Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus.
  311. (2002). Restricted feeding induces daily expression of clock genes and Pai-1 mRNA in the heart of Clock mutant mice.
  312. (2000). Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus.
  313. (2007). Return to the fetal gene program protects the stressed heart: a strong hypothesis.
  314. (2006). Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions.
  315. (2003). Rhythmic histone acetylation underlies transcription in the mammalian circadian clock.
  316. (2000). Role of DBP in the circadian oscillatory mechanism.
  317. (2006). Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.
  318. (2004). rVISTA 2.0: evolutionary analysis of transcription factor binding sites.
  319. (1996). S.J.: Gel Electrophoresis Under Denaturing Conditions, Protein Methods.
  320. (2005). Ser-557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by glycogen synthase kinase-3 beta.
  321. (2004). Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase.
  322. (1997). SHARPs: mammalian enhancer-ofsplit- and hairy-related proteins coupled to neuronal stimulation.
  323. (1999). Signaling pathways for cardiac hypertrophy and failure.
  324. (2005). Significance of the transcription factor KLF5 in cardiovascular remodeling.
  325. (2008). SIRT1 is a circadian deacetylase for core clock components.
  326. (2003). Sizing up the heart: development redux in disease.
  327. (2000). Squaring up the E-box.
  328. (2004). Subcellular localization and regulation of hypoxia-inducible factor-2alpha in vascular endothelial cells.
  329. (1991). Suprachiasmatic Nucleus: The Mind's Clock.
  330. (1998). Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene.
  331. (2007). System-driven and oscillatordependent circadian transcription in mice with a conditionally active liver clock.
  332. (2005). System-level identification of transcriptional circuits underlying mammalian circadian clocks.
  333. (2004). The "CholesteROR" protective pathway in the vascular system.
  334. (2002). The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer.
  335. (2000). The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors.
  336. (1998). The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors.
  337. (2003). The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system.
  338. (2006). The circadian clock within the cardiomyocyte is essential for responsiveness of the heart to fatty acids.
  339. (2006). The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function.
  340. (2005). The circadian cycle: daily rhythms from behaviour to genes.
  341. (2006). The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells.
  342. (2002). The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo.
  343. (2006). The circadian protein Clock localizes to the sarcomeric Z-disk and is a sensor of myofilament cross-bridge activity in cardiac myocytes.
  344. (2002). The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon.
  345. (2006). The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock.
  346. (2007). The disruption of circadian clockwork in differentiating cells from rat reproductive tissues as identified by in vitro real-time monitoring system.
  347. (2002). The functional efficiency of lipogenic and cholesterogenic gene expression in normal mice and in mice lacking the peroxisomal proliferatoractivated receptor-alpha (PPAR-alpha).
  348. (2004). The gene encoding human retinoic acid-receptor-related orphan receptor alpha is a target for hypoxia-inducible factor 1.
  349. (1998). The hypoxiaresponsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development.
  350. (2005). The intrinsic circadian clock within the cardiomyocyte.
  351. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control.
  352. (1989). The Neurospora clock gene frequency shares a sequence element with the Drosophila clock gene period.
  353. (1998). The nuclear receptors peroxisome proliferator-activated receptor alpha and Reverbalpha mediate the species-specific regulation of apolipoprotein A-I expression by fibrates.
  354. (2006). The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1.
  355. (2002). The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.
  356. (2003). The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgammainduced adipocyte differentiation.
  357. (2007). The orphan nuclear receptor Rev-erbalpha: a transcriptional link between circadian rhythmicity and cardiometabolic disease.
  358. (2005). The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol
  359. (2004). The orphan receptor Rev-erb{alpha} gene is a target of the circadian clock pacemaker.
  360. The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells.
  361. (1998). The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease.
  362. (2007). The PPAR regulatory system in cardiac physiology and disease.
  363. (1992). The role of the transcriptional activator protein DBP in circadian liver gene expression.
  364. (2000). The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling.
  365. (2004). The transcriptional repressor STRA13 regulates a subset of peripheral circadian outputs.
  366. (1993). The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI1) gene respond differently to interleukin-1 in HepG2 cells.
  367. (2001). The upstream stimulatory factor-2a inhibits plasminogen activator inhibitor-1 gene expression by binding to a promoter element adjacent to the hypoxia-inducible factor-1 binding site.
  368. (2000). The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression.
  369. (2002). Time after time: inputs to and outputs from the mammalian circadian oscillators.
  370. (2001). Time zones: a comparative genetics of circadian clocks.
  371. (1996). Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice.
  372. (2005). Tissuespecific disruption of rhythmic expression of Dec1 and Dec2 in clock mutant mice.
  373. (1996). Transcription of tufA and other chloroplast-encoded genes is controlled by a circadian clock in Chlamydomonas.
  374. (2004). Transcription, translation, degradation, and circadian clock.
  375. (2004). Transcriptional oscillation of canonical clock genes in mouse peripheral tissues.
  376. (2001). Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha.
  377. (1998). Transcriptionally active heterodimer formation of an
  378. Uncoupling protein 3 transcription is regulated by peroxisome proliferatoractivated receptor (alpha) in the adult rodent heart.
  379. (2003). Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes.
  380. (2005). Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia.
  381. (2004). Uncoupling proteins in human heart.
  382. (2005). Upstream stimulating factors: highly versatile stress-responsive transcription factors.
  383. (2003). Upstream stimulatory factor activates the vasopressin promoter via multiple motifs, including a non-canonical Ebox.
  384. (2005). Upstream stimulatory factor regulates E box-dependent PAI-1 transcription in human epidermal keratinocytes.
  385. (2008). Vascular circadian rhythms in a mouse vascular smooth muscle cell line
  386. (2002). Vasodilatation in the Management of Acute CHF study: Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial.
  387. (2006). When the Clock stops ticking, metabolic syndrome explodes.
  388. (2003). Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs.
  389. (2002). X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.