Malfunction of the circadian timing system may result in cardiovascular and metabolic diseases, and conversely, these diseases can impair the circadian system. The aim of this study was to reveal whether the functional state of the circadian system of spontaneously hypertensive rats (SHR) differs from that of control Wistar rat. This study is the first to analyze the function of the circadian system of SHR in its complexity, i.e., of the central clock in the suprachiasmatic nuclei (SCN) as well as of the peripheral clocks. The functional properties of the SCN clock were estimated by behavioral output rhythm in locomotor activity and daily profiles of clock gene expression in the SCN determined by in situ hybridization. The function of the peripheral clocks was assessed by daily profiles of clock gene expression in the liver and colon by RT-PCR and in vitro using real time recording of Bmal1-dLuc reporter. The potential impact of the SHR phenotype on circadian control of the metabolic pathways was estimated by daily profiles of metabolism-relevant gene expression in the liver and colon. The results revealed that SHR exhibited an early chronotype, because the central SCN clock was phase advanced relative to light/dark cycle and the SCN driven output rhythm ran faster compared to Wistar rats. Moreover, the output rhythm was dampened. The SHR peripheral clock reacted to the dampened SCN output with tissue-specific consequences. In the colon of SHR the clock function was severely altered, whereas the differences are only marginal in the liver. These changes may likely result in a mutual desynchrony of circadian oscillators within the circadian system of SHR, thereby potentially contributing to metabolic pathology of the strain. The SHR may thus serve as a valuable model of human circadian disorders originating in poor synchrony of the circadian system with external light/dark regime.

Department of Neurohumoral Regulations Institute of Physiology Academy of Sciences of the Czech Republic v v i Prague Czech Republic

Zobrazit více v PubMed

Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27: 282–293. PubMed

Pravenec M, Zidek V, Landa V, Simakova M, Mlejnek P, et al. (2004) Genetic analysis of “metabolic syndrome” in the spontaneously hypertensive rat. Physiol Res 53 Suppl 1 S15–22. PubMed

Dibner C, Schibler U, Albrecht U (2010) The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol 72: 517–549. PubMed

Reppert SM, Weaver DR (2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63: 647–676. PubMed

Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, et al. (2000) Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103: 1009–1017. PubMed PMC

Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, et al. (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280: 1564–1569. PubMed

Hogenesch JB, Gu YZ, Jain S, Bradfield CA (1998) The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc Natl Acad Sci U S A 95: 5474–5479. PubMed PMC

King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka H, et al. (1997) Postional cloning of the mouse circadian clock gene. Cell 89: 641–653. PubMed PMC

Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, et al. (1999) mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98: 193–205. PubMed

Okamura H, Miyake S, Sumi Y, Yamaguchi S, Yasui A, et al. (1999) Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 286: 2531–2534. PubMed

Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, et al. (2000) Interacting molecular loops in the mammalian circadian clock. Science 288: 1013–1019. PubMed

Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, et al. (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251–260. PubMed

Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, et al. (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43: 527–537. PubMed

Bellet MM, Sassone-Corsi P (2010) Mammalian circadian clock and metabolism - the epigenetic link. J Cell Sci 123: 3837–3848. PubMed PMC

Asher G, Schibler U (2011) Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab 13: 125–137. PubMed

Bass J, Takahashi JS (2010) Circadian integration of metabolism and energetics. Science 330: 1349–1354. PubMed PMC

Welsh DK, Takahashi JS, Kay SA (2010) Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol 72: 551–577. PubMed PMC

Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, et al. (2010) Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat Med 16: 67–74. PubMed

Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, et al. (2010) Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466: 627–631. PubMed PMC

Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, et al. (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485: 62–68. PubMed PMC

Kaneko K, Yamada T, Tsukita S, Takahashi K, Ishigaki Y, et al. (2009) Obesity alters circadian expressions of molecular clock genes in the brainstem. Brain Res 1263: 58–68. PubMed

Ando H, Kumazaki M, Motosugi Y, Ushijima K, Maekawa T, et al. (2011) Impairment of peripheral circadian clocks precedes metabolic abnormalities in ob/ob mice. Endocrinology 152: 1347–1354. PubMed

Hsieh MC, Yang SC, Tseng HL, Hwang LL, Chen CT, et al. (2010) Abnormal expressions of circadian-clock and circadian clock-controlled genes in the livers and kidneys of long-term, high-fat-diet-treated mice. Int J Obes (Lond) 34: 227–239. PubMed

Takahashi JS, Hong HK, Ko CH, McDearmon EL (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9: 764–775. PubMed PMC

Lemmer B, Mattes A, Bohm M, Ganten D (1993) Circadian blood pressure variation in transgenic hypertensive rats. Hypertension 22: 97–101. PubMed

Carley DW, Trbovic S, Radulovacki M (1996) Sleep apnea in normal and REM sleep-deprived normotensive Wistar-Kyoto and spontaneously hypertensive (SHR) rats. Physiol Behav 59: 827–831. PubMed

Peters RV, Zoeller RT, Hennessey AC, Stopa EG, Anderson G, et al. (1994) The control of circadian rhythms and the levels of vasoactive intestinal peptide mRNA in the suprachiasmatic nucleus are altered in spontaneously hypertensive rats. Brain Res 639: 217–227. PubMed

Maywood ES, O’Neill JS, Chesham JE, Hastings MH (2007) Minireview: The circadian clockwork of the suprachiasmatic nuclei–analysis of a cellular oscillator that drives endocrine rhythms. Endocrinology 148: 5624–5634. PubMed

Naito Y, Tsujino T, Kawasaki D, Okumura T, Morimoto S, et al. (2003) Circadian gene expression of clock genes and plasminogen activator inhibitor-1 in heart and aorta of spontaneously hypertensive and Wistar-Kyoto rats. J Hypertens 21: 1107–1115. PubMed

Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, et al. (2007) Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A 104: 14412–14417. PubMed PMC

Yin L, Wu N, Lazar MA (2010) Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal 8: e001. PubMed PMC

Sumova A, Jac M, Sladek M, Sauman I, Illnerova H (2003) Clock gene daily profiles and their phase relationship in the rat suprachiasmatic nucleus are affected by photoperiod. J Biol Rhythms 18: 134–144. PubMed

Sladek M, Jindrakova Z, Bendova Z, Sumova A (2007) Postnatal ontogenesis of the circadian clock within the rat liver. Am J Physiol Regul Integr Comp Physiol 292: R1224–1229. PubMed

Sladek M, Rybova M, Jindrakova Z, Zemanova Z, Polidarova L, et al. (2007) Insight into the circadian clock within rat colonic epithelial cells. Gastroenterology 133: 1240–1249. PubMed

Reddy AB, Karp NA, Maywood ES, Sage EA, Deery M, et al. (2006) Circadian orchestration of the hepatic proteome. Curr Biol 16: 1107–1115. PubMed

Sato TK, Yamada RG, Ukai H, Baggs JE, Miraglia LJ, et al. (2006) Feedback repression is required for mammalian circadian clock function. Nat Genet 38: 312–319. PubMed PMC

Sagvolden T, Johansen EB, Woien G, Walaas SI, Storm-Mathisen J, et al. (2009) The spontaneously hypertensive rat model of ADHD–the importance of selecting the appropriate reference strain. Neuropharmacology 57: 619–626. PubMed PMC

Berger DF, Starzec JJ (1988) Contrasting lever-press avoidance behaviors of spontaneously hypertensive and normotensive rats (Rattus norvegicus). J Comp Psychol 102: 279–286. PubMed

Pare WP (1989) Stress ulcer and open-field behavior of spontaneously hypertensive, normotensive, and Wistar rats. Pavlov J Biol Sci 24: 54–57. PubMed

Rosenwasser AM, Plante L (1993) Circadian activity rhythms in SHR and WKY rats: strain differences and effects of clonidine. Physiol Behav 53: 23–29. PubMed

Edgar DM, Martin CE, Dement WC (1991) Activity feedback to the mammalian circadian pacemaker: influence on observed measures of rhythm period length. J Biol Rhythms 6: 185–199. PubMed

Leaton RN, Cassella JV, Whitehorn D (1983) Locomotor activity, auditory startle and shock thresholds in spontaneously hypertensive rats. Physiol Behav 31: 103–109. PubMed

van den Buuse M (1994) Circadian rhythms of blood pressure, heart rate, and locomotor activity in spontaneously hypertensive rats as measured with radio-telemetry. Physiol Behav 55: 783–787. PubMed

Maywood ES, Mrosovsky N, Field MD, Hastings MH (1999) Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock. Proc Natl Acad Sci U S A 96: 15211–15216. PubMed PMC

Cui H, Kohsaka A, Waki H, Bhuiyan ME, Gouraud SS, et al. (2011) Metabolic cycles are linked to the cardiovascular diurnal rhythm in rats with essential hypertension. PLoS One 6: e17339. PubMed PMC

Kornmann B, Schaad O, Bujard H, Takahashi JS, Schibler U (2007) System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol 5: e34. PubMed PMC

Atanur SS, Birol I, Guryev V, Hirst M, Hummel O, et al. (2010) The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome Res 20: 791–803. PubMed PMC

Ripperger JA, Schibler U (2006) Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 38: 369–374. PubMed

Oishi K, Shirai H, Ishida N (2005) CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor alpha (PPARalpha) in mice. Biochem J 386: 575–581. PubMed PMC

Fajas L, Schoonjans K, Gelman L, Kim JB, Najib J, et al. (1999) Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism. Mol Cell Biol 19: 5495–5503. PubMed PMC

Irrcher I, Ljubicic V, Kirwan AF, Hood DA (2008) AMP-activated protein kinase-regulated activation of the PGC-1alpha promoter in skeletal muscle cells. PLoS One 3: e3614. PubMed PMC

Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, et al. (2003) Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255–259. PubMed

Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, et al... (2009) Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis. Science. PubMed PMC

Gachon F, Olela FF, Schaad O, Descombes P, Schibler U (2006) The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab 4: 25–36. PubMed

Gachon F, Fonjallaz P, Damiola F, Gos P, Kodama T, et al. (2004) The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev 18: 1397–1412. PubMed PMC

Saito H, Terada T, Shimakura J, Katsura T, Inui K (2008) Regulatory mechanism governing the diurnal rhythm of intestinal H+/peptide cotransporter 1 (PEPT1). Am J Physiol Gastrointest Liver Physiol 295: G395–402. PubMed

Duez H, van der Veen JN, Duhem C, Pourcet B, Touvier T, et al. (2008) Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha. Gastroenterology 135: 689–698. PubMed

Tong X, Muchnik M, Chen Z, Patel M, Wu N, et al. (2010) Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding. J Biol Chem 285: 36401–36409. PubMed PMC

Ohno T, Onishi Y, Ishida N (2007) A novel E4BP4 element drives circadian expression of mPeriod2. Nucleic Acids Res 35: 648–655. PubMed PMC

Murakami Y, Higashi Y, Matsunaga N, Koyanagi S, Ohdo S (2008) Circadian clock-controlled intestinal expression of the multidrug-resistance gene mdr1a in mice. Gastroenterology 135: 1636–1644 e1633. PubMed

Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P (2009) Circadian Control of the NAD+ Salvage Pathway by CLOCK-SIRT1. Science. PubMed PMC

Gachon F, Leuenberger N, Claudel T, Gos P, Jouffe C, et al. (2011) Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor alpha (PPARalpha) activity. Proc Natl Acad Sci U S A 108: 4794–4799. PubMed PMC

Kawai M, Rosen CJ (2010) PPARgamma: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol 6: 629–636. PubMed PMC

Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, et al. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458: 1056–1060. PubMed PMC

Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, et al. (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437–440. PubMed PMC

Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, et al. (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317–328. PubMed

Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, et al. (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134: 329–340. PubMed PMC

Liu C, Li S, Liu T, Borjigin J, Lin JD (2007) Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 447: 477–481. PubMed

Polidarova L, Sotak M, Sladek M, Pacha J, Sumova A (2009) Temporal Gradient in the Clock Gene and Cell-Cycle Checkpoint Kinase Wee1 Expression along the Gut. Chronobiology International 26: 607–620. PubMed

Xia Y, Wang J, Liu TJ, Yung WK, Hunter T, et al. (2007) c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Mol Cell 25: 219–232. PubMed PMC

Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji-Adele A, et al. (2008) Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456: 997–1000. PubMed PMC

Zhang F, Shi Y, Wang L, Sriram S (2011) Role of HDAC3 on p53 expression and apoptosis in T cells of patients with multiple sclerosis. PLoS One 6: e16795. PubMed PMC

Feng D, Liu T, Sun Z, Bugge A, Mullican SE, et al. (2011) A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331: 1315–1319. PubMed PMC

Li D, Wang X, Ren W, Ren J, Lan X, et al. (2011) High expression of liver histone deacetylase 3 contributes to high-fat-diet-induced metabolic syndrome by suppressing the PPAR-gamma and LXR-alpha-pathways in E3 rats. Mol Cell Endocrinol 344: 69–80. PubMed

He Q, Gao Z, Yin J, Zhang J, Yun Z, et al. (2011) Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab 300: E877–885. PubMed PMC

Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8: 705–713. PubMed

Shen GM, Zhang FL, Liu XL, Zhang JW (2010) Hypoxia-inducible factor 1-mediated regulation of PPP1R3C promotes glycogen accumulation in human MCF-7 cells under hypoxia. FEBS Lett 584: 4366–4372. PubMed

Ceulemans H, Bollen M (2004) Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev 84: 1–39. PubMed

Lee HM, Chen R, Kim H, Etchegaray JP, Weaver DR, et al. (2011) The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1. Proc Natl Acad Sci U S A 108: 16451–16456. PubMed PMC

Schmutz I, Wendt S, Schnell A, Kramer A, Mansuy IM, et al. (2011) Protein phosphatase 1 (PP1) is a post-translational regulator of the mammalian circadian clock. PLoS One 6: e21325. PubMed PMC

Polidarova L, Sladek M, Sotak M, Pacha J, Sumova A (2011) Hepatic, Duodenal, and Colonic Circadian Clocks Differ in their Persistence under Conditions of Constant Light and in their Entrainment by Restricted Feeding. Chronobiology International 28: 204–215. PubMed

Chronodisruption that dampens output of the central clock abolishes rhythms in metabolome profiles and elevates acylcarnitine levels in the liver of female rats

Circadian Disruption as a Risk Factor for Development of Cardiovascular and Metabolic Disorders - From Animal Models to Human Population

The Circadian Clock of Polarized Microglia and Its Interaction with Mouse Brain Oscillators

Misaligned feeding schedule elicits divergent circadian reorganizations in endo- and exocrine pancreas clocks

Chronotype assessment via a large scale socio-demographic survey favours yearlong Standard time over Daylight Saving Time in central Europe

Circadian alignment in a foster mother improves the offspring's pathological phenotype

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity

Entrainment of spontaneously hypertensive rat fibroblasts by temperature cycles

Increased sensitivity of the circadian system to temporal changes in the feeding regime of spontaneously hypertensive rats - a potential role for Bmal2 in the liver