The Journal of Physiological Sciences

, Volume 68, Issue 4, pp 441–454 | Cite as

β-Adrenergic signaling, monoamine oxidase A and antioxidant defence in the myocardium of SHR and SHR-mtBN conplastic rat strains: the effect of chronic hypoxia

  • Klara Hahnova
  • Iveta Brabcova
  • Jan Neckar
  • Romana Weissova
  • Anna Svatonova
  • Olga Novakova
  • Jitka Zurmanova
  • Martin Kalous
  • Jan Silhavy
  • Michal Pravenec
  • Frantisek Kolar
  • Jiri NovotnyEmail author
Original Paper


The β-adrenergic signaling pathways and antioxidant defence mechanisms play important roles in maintaining proper heart function. Here, we examined the effect of chronic normobaric hypoxia (CNH, 10% O2, 3 weeks) on myocardial β-adrenergic signaling and selected components of the antioxidant system in spontaneously hypertensive rats (SHR) and in a conplastic SHR-mtBN strain characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischemia–resistant Brown Norway strain. Our investigations revealed some intriguing differences between the two strains at the level of β-adrenergic receptors (β-ARs), activity of adenylyl cyclase (AC) and monoamine oxidase A (MAO-A), as well as distinct changes after CNH exposure. The β2-AR/β1-AR ratio was significantly higher in SHR-mtBN than in SHR, apparently due to increased expression of β2-ARs. Adaptation to hypoxia elevated β2-ARs in SHR and decreased the total number of β-ARs in SHR-mtBN. In parallel, the ability of isoprenaline to stimulate AC activity was found to be higher in SHR-mtBN than that in SHR. Interestingly, the activity of MAO-A was notably lower in SHR-mtBN than in SHR, and it was markedly elevated in both strains after exposure to hypoxia. In addition to that, CNH markedly enhanced the expression of catalase and aldehyde dehydrogenase-2 in both strains, and decreased the expression of Cu/Zn superoxide dismutase in SHR. Adaptation to CNH intensified oxidative stress to a similar extent in both strains and elevated the IL-10/TNF-α ratio in SHR-mtBN only. These data indicate that alterations in the mitochondrial genome can result in peculiar changes in myocardial β-adrenergic signaling, MAO-A activity and antioxidant defence and may, thus, affect the adaptive responses to hypoxia.


SHR Mitochondrial genome Myocardium β-adrenergic receptors Adenylyl cyclase Monoamine oxidase A Antioxidant defence Chronic hypoxia 



This work was supported by Grant 13-10267 from the Czech Science Foundation, Grant 1214214 from the Charles University Grant Agency, and by the institutional research projects no. 67985823 (Institute of Physiology, CAS) and SVV-260434/2017 (Charles University in Prague). MP was supported by Grants LL1204 (within the ERC CZ program) from the Ministry of Education, Youth and Sports and P301/12/0696 from the Czech Science Foundation.

Compliance with ethical standards

Conflict of interests

The authors have no conflict of interest to declare.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

12576_2017_546_MOESM1_ESM.docx (87 kb)
Supplementary material 1 (DOCX 87 kb)
12576_2017_546_MOESM2_ESM.docx (316 kb)
Supplementary material 2 (DOCX 315 kb)
12576_2017_546_MOESM3_ESM.docx (127 kb)
Supplementary material 3 (DOCX 127 kb)


  1. 1.
    Hajri T, Ibrahimi A, Coburn CT, Knapp FF, Kurtz T, Pravenec M, Abumrad NA (2001) Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. J Biol Chem 276:23661–23666CrossRefGoogle Scholar
  2. 2.
    Itter G, Jung W, Juretschke P, Schoelkens BA, Linz W (2004) A model of chronic heart failure in spontaneous hypertensive rats (SHR). Lab Anim 38:138–148CrossRefGoogle Scholar
  3. 3.
    Penna C, Pasqua T, Amelio D, Perrelli MG, Angotti C, Tullio F, Mahata SK, Tota B, Pagliaro P, Cerra MC, Angelone T (2014) Catestatin increases the expression of anti-apoptotic and pro-angiogenetic factors in the post-ischemic hypertrophied heart of SHR. PLoS One 9:e102536CrossRefGoogle Scholar
  4. 4.
    Ravingerová T, Bernátová I, Matejíková J, Ledvényiová V, Nemčeková M, Pecháňová O, Tribulová N, Slezák J (2011) Impaired cardiac ischemic tolerance in spontaneously hypertensive rats is attenuated by adaptation to chronic and acute stress. Exp Clin Cardiol 16:e23–e29PubMedPubMedCentralGoogle Scholar
  5. 5.
    Kolar F, Parratt JR (1997) Antiarrhythmic effect of ischemic preconditioning in hearts of spontaneously hypertensive rats. Exp Clin Cardiol 2:124–128Google Scholar
  6. 6.
    Neckář J, Šilhavy J, Zídek V, Landa V, Mlejnek P, Šimáková M, Seidman JG, Seidman C, Kazdová L, Klevstig M, Novák F, Vecka M, Papoušek F, Houštěk J, Drahota Z, Kurtz TW, Kolář F, Pravenec M (2012) CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genom 44:173–182CrossRefGoogle Scholar
  7. 7.
    Klevstig M, Manakov D, Kasparova D, Brabcova I, Papousek F, Zurmanova J, Zidek V, Silhavy J, Neckar J, Pravenec M, Kolar F, Novakova O, Novotny J (2013) Transgenic rescue of defective Cd36 enhances myocardial adenylyl cyclase signaling in spontaneously hypertensive rats. Pflugers Arch 465:1477–1486CrossRefGoogle Scholar
  8. 8.
    Florea SM, Blatter LA (2012) Regulation of cardiac alternans by β-adrenergic signaling pathways. Am J Physiol Heart Circ Physiol 303:H1047–H1056CrossRefGoogle Scholar
  9. 9.
    Frances C, Nazeyrollas P, Prevost A, Moreau F, Pisani J, Davani S, Kantelip JP, Millart H (2003) Role of beta 1- and beta 2-adrenoceptor subtypes in preconditioning against myocardial dysfunction after ischemia and reperfusion. J Cardiovasc Pharmacol 41:396–405CrossRefGoogle Scholar
  10. 10.
    Tong H, Bernstein D, Murphy E, Steenbergen C (2005) The role of beta-adrenergic receptor signaling in cardioprotection. FASEB J 19:983–985CrossRefGoogle Scholar
  11. 11.
    Salie R, Moolman JA, Lochner A (2011) The role of β-adrenergic receptors in the cardioprotective effects of beta-preconditioning (βPC). Cardiovasc Drugs Ther 25:31–46CrossRefGoogle Scholar
  12. 12.
    Mader SL, Downing CL, Van Lunteren E (1991) Effect of age and hypoxia on beta-adrenergic receptors in rat heart. J Appl Physiol 71:2094–2098CrossRefGoogle Scholar
  13. 13.
    Kacimi R, Richalet JP, Corsin A, Abousahl I, Crozatier B (1992) Hypoxia-induced downregulation of beta-adrenergic receptors in rat heart. J Appl Physiol 73:1377–1382CrossRefGoogle Scholar
  14. 14.
    Mardon K, Merlet P, Syrota A, Mazière B (1998) Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats. J Appl Physiol 85:890–897CrossRefGoogle Scholar
  15. 15.
    León-Velarde F, Bourin MC, Germack R, Mohammadi K, Crozatier B, Richalet JP (2001) Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion. Am J Physiol Regul Integr Comp Physiol 280:R274–R281CrossRefGoogle Scholar
  16. 16.
    Hrbasová M, Novotny J, Hejnová L, Kolár F, Neckár J, Svoboda P (2003) Altered myocardial Gs protein and adenylyl cyclase signaling in rats exposed to chronic hypoxia and normoxic recovery. J Appl Physiol 94:2423–2432CrossRefGoogle Scholar
  17. 17.
    Johnson TS, Young JB, Landsberg L (1983) Sympathoadrenal responses to acute and chronic hypoxia in the rat. J Clin Invest 71:1263–1272CrossRefGoogle Scholar
  18. 18.
    Andersson DC, Fauconnier J, Yamada T, Lacampagne A, Zhang SJ, Katz A, Westerblad H (2011) Mitochondrial production of reactive oxygen species contributes to the β-adrenergic stimulation of mouse cardiomycytes. J Physiol 589:1791–1801CrossRefGoogle Scholar
  19. 19.
    Mallet RT, Ryou MG, Williams AG, Howard L, Downey HF (2006) β1-Adrenergic receptor antagonism abrogates cardioprotective effects of intermittent hypoxia. Basic Res Cardiol 101:436–446CrossRefGoogle Scholar
  20. 20.
    Zuo L, Roberts WJ, Tolomello RC, Goins AR (2013) Ischemic and hypoxic preconditioning protect cardiac muscles via intracellular ROS signaling. Front Biol 8:305–311CrossRefGoogle Scholar
  21. 21.
    Kolár F, Jezková J, Balková P, Breh J, Neckár J, Novák F, Nováková O, Tomásová H, Srbová M, Ost’ádal B, Wilhelm J, Herget J (2007) Role of oxidative stress in PKC-delta upregulation and cardioprotection induced by chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol 292:H224–H230CrossRefGoogle Scholar
  22. 22.
    Kasparova D, Neckar J, Dabrowska L, Novotny J, Mraz J, Kolar F, Zurmanova J (2015) Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems. Physiol Genom 47:612–620CrossRefGoogle Scholar
  23. 23.
    Cadenas S, Aragonés J, Landázuri MO (2010) Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease. Cardiovasc Res 88:219–228CrossRefGoogle Scholar
  24. 24.
    Mueller IA, Grim JM, Beers JM, Crockett EL, O’Brien KM (2011) Inter-relationship between mitochondrial function and susceptibility to oxidative stress in red- and white-blooded Antarctic notothenioid fishes. J Exp Biol 214:3732–3741CrossRefGoogle Scholar
  25. 25.
    Cortie CH, Hulbert AJ, Hancock SE, Mitchell TW, McAndrew D, Else PL (2015) Of mice, pigs and humans: an analysis of mitochondrial phospholipids from mammals with very different maximal lifespans. Exp Gerontol 70:135–143CrossRefGoogle Scholar
  26. 26.
    Kelly RD, Rodda AE, Dickinson A, Mahmud A, Nefzger CM, Lee W, Forsythe JS, Polo JM, Trounce IA, McKenzie M, Nisbet DR, St John JC (2013) Mitochondrial DNA haplotypes define gene expression patterns in pluripotent and differentiating embryonic stem cells. Stem Cells 31:703–716CrossRefGoogle Scholar
  27. 27.
    Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407CrossRefGoogle Scholar
  28. 28.
    Neckář J, Svatoňová A, Weissová R, Drahota Z, Zajíčková P, Brabcová I, Kolář D, Alánová P, Vašinová J, Šilhavý J, Hlaváčková M, Tauchmannová K, Milerová M, Ošťádal B, Červenka L, Žurmanová J, Kalous M, Nováková O, Novotný J, Pravenec M, Kolář F (2017) Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats. Clin Sci 131:865–881CrossRefGoogle Scholar
  29. 29.
    Anderson EJ, Efird JT, Davies SW, O’Neal WT, Darden TM, Thayne KA, Katunga LA, Kindell LC, Ferguson TB, Anderson CA, Chitwood WR, Koutlas TC, Williams JM, Rodriguez E, Kypson AP (2014) Monoamine oxidase is a major determinant of redox balance in human atrial myocardium and is associated with postoperative atrial fibrillation. J Am Heart Assoc 3:e000713CrossRefGoogle Scholar
  30. 30.
    Waskova-Arnostova P, Elsnicova B, Kasparova D, Sebesta O, Novotny J, Neckar J, Kolar F, Zurmanova J (2013) Right-to-left ventricular differences in the expression of mitochondrial hexokinase and phosphorylation of Akt. Cell Physiol Biochem 31:66–79CrossRefGoogle Scholar
  31. 31.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45CrossRefGoogle Scholar
  32. 32.
    Hahnova K, Kasparova D, Zurmanova J, Neckar J, Kolar F, Novotny J (2016) β-Adrenergic signaling in rat heart is similarly affected by continuous and intermittent normobaric hypoxia. Gen Physiol Biophys 35:165–167CrossRefGoogle Scholar
  33. 33.
    Ihnatovych I, Hejnová L, Kostrnová A, Mares P, Svoboda P, Novotný J (2001) Maturation of rat brain is accompanied by differential expression of the long and short splice variants of G(s)alpha protein: identification of cytosolic forms of G(s)alpha. J Neurochem 79:88–97CrossRefGoogle Scholar
  34. 34.
    Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ (2005) The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 518:40–46CrossRefGoogle Scholar
  35. 35.
    Novotny J, Bourová L, Kolár F, Svoboda P (2001) Membrane-Bound and cytosolic forms of heterotrimeric G proteins in young and adult rat myocardium: influence of neonatal hypo- and hyperthyroidism. J Cell Biochem 82:215–224CrossRefGoogle Scholar
  36. 36.
    Pilz J, Meineke I, Gleiter CH (2000) Measurement of free and bound malondialdehyde in plasma by high-performance liquid chromatography as the 2,4-dinitrophenylhydrazine derivative. J Chromatogr B Biomed Sci Appl 742:315–325CrossRefGoogle Scholar
  37. 37.
    Chytilová A, Borchert GH, Mandíková-Alánová P, Hlaváčková M, Kopkan L, Khan MA, Imig JD, Kolář F, Neckář J (2015) Tumour necrosis factor-α contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia. Acta Physiol 214:97–108CrossRefGoogle Scholar
  38. 38.
    Giannuzzi CE, Seidler FJ, Slotkin TA (1995) Beta-adrenoceptor control of cardiac adenylyl cyclase during development: agonist pretreatment in the neonate uniquely causes heterologous sensitization, not desensitization. Brain Res 694:271–278CrossRefGoogle Scholar
  39. 39.
    Mieno S, Horimoto H, Sawa Y, Watanabe F, Furuya E, Horimoto S, Kishida K, Sasaki S (2005) Activation of beta2-adrenergic receptor plays a pivotal role in generating the protective effect of ischemic preconditioning in rat hearts. Scand Cardiovasc J 39:313–319CrossRefGoogle Scholar
  40. 40.
    Fajardo G, Zhao M, Berry G, Wong LJ, Mochly-Rosen D, Bernstein D (2011) β2-adrenergic receptors mediate cardioprotection through crosstalk with mitochondrial cell death pathways. J Mol Cell Cardiol 51:781–789CrossRefGoogle Scholar
  41. 41.
    Schömig A, Fischer S, Kurz T, Richardt G, Schömig E (1987) Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart: mechanism and metabolic requirements. Circ Res 60:194–205CrossRefGoogle Scholar
  42. 42.
    Kaludercic N, Carpi A, Menabò R, Di Lisa F, Paolocci N (2011) Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 1813:1323–1332CrossRefGoogle Scholar
  43. 43.
    Dănilă MD, Privistirescu AI, Mirica SN, Sturza A, Ordodi V, Noveanu L, Duicu OM, Muntean DM (2015) Acute inhibition of monoamine oxidase and ischemic preconditioning in isolated rat hearts: interference with postischemic functional recovery but no effect on infarct size reduction. Can J Physiol Pharmacol 93:819–825CrossRefGoogle Scholar
  44. 44.
    Maher JT, Deniiston JC, Wolfe DL, Cymerman A (1978) Mechanism of the attenuated cardiac response to beta-adrenergic stimulation in chronic hypoxia. J Appl Physiol Respir Environ Exerc Physiol 44:647–651PubMedGoogle Scholar
  45. 45.
    Shatemirova KK, Zelenshchikova VA, Min’ko IV (1990) Catalytic properties of monoamine oxidases during adaptation to altitude chamber hypoxia. Kosm Biol Aviakosm Med 24:54–56PubMedGoogle Scholar
  46. 46.
    Yan F, Mu Y, Yan G, Liu J, Shen J, Luo G (2010) Antioxidant enzyme mimics with synergism. Mini Rev Med Chem 10:342–356CrossRefGoogle Scholar
  47. 47.
    Nakanishi K, Tajima F, Nakamura A, Yagura S, Ookawara T, Yamashita H, Suzuki K, Taniguchi N, Ohno H (1995) Effects of hypobaric hypoxia on antioxidant enzymes in rats. J Physiol 489(Pt 3):869–876CrossRefGoogle Scholar
  48. 48.
    Neckár J, Borchert GH, Hlousková P, Mícová P, Nováková O, Novák F, Hroch M, Papousek F, Ost’ádal B, Kolár F (2013) Brief daily episode of normoxia inhibits cardioprotection conferred by chronic continuous hypoxia. Role of oxidative stress and BKCa channels. Curr Pharm Des 19:6880–6889CrossRefGoogle Scholar
  49. 49.
    Bu HM, Yang CY, Wang ML, Ma HJ, Sun H, Zhang Y (2015) K(ATP) channels and MPTP are involved in the cardioprotection bestowed by chronic intermittent hypobaric hypoxia in the developing rat. J Physiol Sci 65:367–376CrossRefGoogle Scholar
  50. 50.
    Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321:1493–1495CrossRefGoogle Scholar
  51. 51.
    Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M (2008) Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. J Biol Chem 283:33554–33562CrossRefGoogle Scholar
  52. 52.
    Chau CM, Evans MJ, Scarpulla RC (1992) Nuclear respiratory factor 1 activation sites in genes encoding the gamma-subunit of ATP synthase, eukaryotic initiation factor 2 alpha, and tyrosine aminotransferase. Specific interaction of purified NRF-1 with multiple target genes. J Biol Chem 267:6999–7006PubMedGoogle Scholar
  53. 53.
    Evans MJ, Scarpulla RC (1990) NRF-1: a trans-activator of nuclear-encoded respiratory genes in animal cells. Genes Dev 4:1023–1034CrossRefGoogle Scholar
  54. 54.
    Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88:611–638CrossRefGoogle Scholar
  55. 55.
    Földes-Papp Z, Domej W, Demel U, Tilz GP (2005) Oxidative stress caused by acute and chronic exposition to altitude. Wien Med Wochenschr 155:136–142CrossRefGoogle Scholar
  56. 56.
    Singh M, Thomas P, Shukla D, Tulsawani R, Saxena S, Bansal A (2013) Effect of subchronic hypobaric hypoxia on oxidative stress in rat heart. Appl Biochem Biotechnol 169:2405–2419CrossRefGoogle Scholar
  57. 57.
    Liu JN, Zhang JX, Lu G, Qiu Y, Yang D, Yin GY, Zhang XL (2010) The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia. Chin Med J 123:74–78PubMedGoogle Scholar
  58. 58.
    Zhou W, Li S, Wan N, Zhang Z, Guo R, Chen B (2012) Effects of various degrees of oxidative stress induced by intermittent hypoxia in rat myocardial tissues. Respirology 17:821–829CrossRefGoogle Scholar
  59. 59.
    Wang WY, Wan WY, Zeng YM, Chen XY, Zhang YX (2013) Effect of Telmisartan on local cardiovascular oxidative stress in mouse under chronic intermittent hypoxia condition. Sleep Breath 17:181–187CrossRefGoogle Scholar
  60. 60.
    Lecour S (2009) Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: does it go beyond the RISK pathway? J Mol Cell Cardiol 47:32–40CrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2017

Authors and Affiliations

  • Klara Hahnova
    • 1
  • Iveta Brabcova
    • 1
  • Jan Neckar
    • 2
  • Romana Weissova
    • 2
  • Anna Svatonova
    • 2
  • Olga Novakova
    • 1
  • Jitka Zurmanova
    • 1
  • Martin Kalous
    • 3
  • Jan Silhavy
    • 2
  • Michal Pravenec
    • 2
  • Frantisek Kolar
    • 2
  • Jiri Novotny
    • 1
    Email author
  1. 1.Department of Physiology, Faculty of ScienceCharles UniversityPragueCzech Republic
  2. 2.Institute of PhysiologyCzech Academy of SciencesPragueCzech Republic
  3. 3.Department of Cell Biology, Faculty of ScienceCharles UniversityPragueCzech Republic

Personalised recommendations