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Upregulation of β3-adrenoceptors—a general marker of and protective mechanism against hypoxia?

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Abstract

β3-Adrenoceptors exhibit a restricted expression pattern, particularly in humans. However, they have been found to be upregulated in various cancers and under several conditions associated with hypoperfusion such as congestive heart failure and diabetes for instance in the heart and other tissues. These conditions are frequently associated with hypoxia. Furthermore, direct induction of hypoxia has consistently been reported to cause upregulation of β3-adrenoceptors across various tissues of multiple species including humans, rats, dogs, and fish. While a canonical hypoxia-response element in the promoter of the human β3-adrenoceptor gene may play a role in this, no such sequence was found in rodent homologs. Moreover, not all upregulation of β3-adrenoceptor protein is accompanied by increased expression of corresponding mRNA, indicating that the upregulation may involve factors other than transcriptional changes. We propose that upregulation of β3-adrenoceptors at the mRNA and/or protein level is a general marker of hypoxic conditions. Moreover, it may be an additional pathway whereby cells and tissues adapt to reduced oxygen levels.

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References

  • Amour J, Loyer X, Le Guen M, Mabrouk N, David J-S, Camors E, Carusio N, Vivien B, Andriantsitohaina R, Heymes C, Riou B (2007) Altered contractile response due to increased β3-adrenoceptor stimulation in diabetic cardiomyopathy. The role of nitric oxide synthase 1–derived nitric oxide. Anesthesiology 107:452–460

  • Amour J, Loyer X, Michelet P, Birenbaum A, Riou B, Heymes C (2008) Preservation of the positive lusitropic effect of β-adrenoceptors stsimulation in diabetic cardiomyopathy. Anesth Analg 107:1130–1138

  • Arioglu E, Guner S, Ozakca I, Altan VM, Ozcelikay AT (2010) The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors. Mol Cell Biochem 335:59–66

  • Arioglu-Inan E, Kaykı-Mutlu G, Michel MC (2019) Cardiac β3-adrenoceptors - a role in human pathophysiology? Br J Pharmacol 176:2482–2495

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barbier J, Rannou-Bekono F, Marchais J, Tanguy S, Carre F (2007) Alterations of b3-adrenoceptors expression and their myocardial functional effects in physiological model of chronic exercise-induced cardiac hypertrophy. Mol Cell Biochem 300:69–75

  • Bayrak S, Balkanci ZD, Pehlivangoglu B, Karabulut I, Karaismailoglu S, Erdem A (2015) Does hypercholesterolemia effect the relaxation of the detrusor smooth muscle in rats? In vitro and in vivo studies. Naunyn Schmiedebergs Arch Pharmacol 388:761–771

    CAS  PubMed  Google Scholar 

  • Birenbaum A, Tesse A, Loyer X, Michelet P, Andriantsitohaina R, Heymes C, Riou B, Amour J (2008) Involvement of β3-adrenoceptor in altered β-adrenergic response in senescent heart. Role of nitric oxide synthase 1–derived nitric oxide. Anesthesiology 109:1045–1053

  • Brodde OE, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51:651–689

    CAS  PubMed  Google Scholar 

  • Calvani M, Pelon F, Comito G, Taddei ML, Moretti S, Innocenti S, Nassini R, Gerlini G, Borgognoni L, Bambi F, Giannoni E, Filippi L, Chiarugi P (2015) Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression. Oncotarget 6:4615–4632

    PubMed  Google Scholar 

  • Calvani M, Cavallini L, Tondo A, Spinelli V, Ricci L, Pasha A, Bruno G, Buonvicino D, Bigagli E, Vignoli M, Bianchini F, Sartiani L, Lodovici M, Semeraro R, Fontani F, De Logu F, Dal Monte M, Chiarugi P, Favre C, Filippi L (2018) β3-Adrenoreceptors control mitochondrial dormancy in melanoma and embryonic stem cells. Oxidative Med Cell Longev 2018:6816508–6816508

    Google Scholar 

  • Calvani M, Bruno G, Dal Monte M, Nassini R, Fontani F, Casini A, Cavallini L, Becatti M, Bianchini F, De Logu F, Forni G, la Marca G, Calorini L, Bagnoli P, Chiarugi P, Pupi A, Azzari C, Geppetti P, Favre C, Filippi L (2019) β3-Adrenoceptor as a potential immuno-suppressor agent in melanoma. Br J Pharmacol 176:2509–2524

    CAS  PubMed  PubMed Central  Google Scholar 

  • Camuzi D, de Amorim ÍSS, Ribeiro Pinto LF, Oliveira Trivilin L, Mencalha AL, Soares Lima SC (2019) Regulation is in the air: the relationship between hypoxia and epigenetics in cancer. Cells 8:300

    CAS  PubMed Central  Google Scholar 

  • Carpene C, Galitzky J, Collon P, Esclapez F, Dauzats M, Lafontan M (1993) Desensitization of beta-1 and beta-2, but not beta-3 adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion. J Pharmacol Exp Ther 265:237–247

    CAS  PubMed  Google Scholar 

  • Chambers J, Park J, Cronk D, Chapman C, Kennedy FR, Wilson S, Milligan G (1994) ß3-Adrenoceptor agonist-induced down-regulation of Gsα and functional desensitization in a Chinese hamster ovary cell line expressing a ß3-adrenoceptor refractory to down-regulation. Biochem J 303:973–978

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng HJ, Zhang ZS, Onishi K, Ukai T, Sane DC, Cheng CP (2001) Upregulation of functional β3-adrenergic receptor in the failing canine myocardium. Circ Res 89:599–606

  • Curran PK, Fishman PH (1996) Endogenous ß3- but not ß1-adrenergic receptors are resistant to agonist-mediated regulation in human SK-N-MC neurotumor cells. Cell Signal 8:355–364

    CAS  PubMed  Google Scholar 

  • Dal Monte M, Casini G, Filippi L, Nicchia GP, Svelto M, Bagnoli P (2013a) Functional involvement of ß3-adrenergic receptors in melanoma growth and vascularization. J Mol Med 91:1407–1419

    CAS  PubMed  Google Scholar 

  • Dal Monte M, Filippi L, Bagnoli P (2013b) Beta3-adrenergic receptors modulate vascular endothelial growth factor release in response to hypoxia through the nitric oxide pathway in mouse retinal explants. Naunyn Schmiedebergs Arch Pharmacol 386:269–278

    CAS  PubMed  Google Scholar 

  • Dal Monte M, Calvani M, Cammalleri M, Favre C, Filippi L, Bagnoli P (2019) β-Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3-adrenoceptors. Br J Pharmacol 176:2496–2508

    CAS  PubMed  Google Scholar 

  • Dinçer ÜD, Bidasee KR, Güner Ş, Tay A, Özçelikay AT, Altan VM (2001) The effect of diabetes on expression of β1-, β2-, and β3-adrenoreceptors in rat hearts. Diabetes 50:455–461

    PubMed  Google Scholar 

  • Dixon TM, Daniel KW, Farmer SR, Collins S (2001) CCAAT/enhancer-binding protein α is required for transcription of the β3-adrenergic receptor gene during adipogenesis. J Biol Chem 276:722–728

    CAS  PubMed  Google Scholar 

  • Dumas M, Dumas J-P, Bardou M, Rochette L, Advenier C, Giudicelli J-F (1998) Influence of β-adrenoceptor agonists on the pulmonary circulation. Effects of a β3-adrenoceptor antagonist, SR 59230A. Eur J Pharmacol 348:223–228

    CAS  PubMed  Google Scholar 

  • Evans BA, Papaioannou M, Bonazzi VR, Summers RJ (1996) Expression of ß3-adrenoceptor mRNA in rat tissues. Br J Pharmacol 117:210–216

    CAS  PubMed  PubMed Central  Google Scholar 

  • García-Prieto J, García-Ruiz JM, Sanz-Rosa D, Pun A, García-Alvarez A, Davidson SM, Fernández-Friera L, Nuno-Ayala M, Fernández-Jiménez R, Bernal JA, Izquierdo-Garcia JL, Jimenez-Borreguero J, Pizarro G, Ruiz-Cabello J, Macaya C, Fuster V, Yellon DM, Ibanez B (2014) β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes. Basic Res Cardiol 109:422

    PubMed  Google Scholar 

  • Gericke A, Böhmer T, Michel MC (2013) ß3-Adrenoceptors, a drug target in ophthalmology? Naunyn Schmiedebergs Arch Pharmacol 386:265–267

    CAS  PubMed  Google Scholar 

  • Gibbs ME, Rodricks CL, Hutchinson DS, Summers RJ, Miller SL (2009) Importance of adrenergic receptors in prenatally induced cognitive impairment in the domestic chick. Int J Dev Neurosci 27:27–35

    CAS  PubMed  Google Scholar 

  • Haley JM, Thackeray JT, Kolajova M, Thorn SL, DaSilva JN (2015) Insulin therapy normalizes reduced myocardial β-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats. Life Sci 132:101–107

  • Himms-Hagen J, Cui J, Danforth E Jr, Taatjes DJ, Lang SS, Waters BL, Claus TH (1994) Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Phys Regul Integr Comp Phys 266:R1371–R1382

    CAS  Google Scholar 

  • Islam F, Qiao B, Smith RA, Gopalan V, Lam AKY (2015) Cancer stem cell: fundamental experimental pathological concepts and updates. Exp Mol Pathol 98:184–191

    CAS  PubMed  Google Scholar 

  • Jiang C, Carillion A, Na N, De Jong A, Feldman S, Lacorte JM, Bonnefont-Rousselot D, Riou B, Amour J (2015) Modification of the β-adrenoceptor pathway in Zucker obese and obese diabetic rat myocardium. Crit Care Med 43:e241–e249

  • Kayki-Mutlu G, Arioglu Inan E, Ozakca I, Ozcelikay AT, Altan VM (2014) β3-Adrenoceptor-mediated responses in diabetic rat heart. Gen Physiol Biophys 33:99–109

  • Kitao N, Hashimoto M (2012) Increased thermogenic capacity of brown adipose tissue under low temperature and its contribution to arousal from hibernation in Syrian hamsters. Am J Physiol Regul Integr Comp Physiol 302:R118–R125

    CAS  PubMed  Google Scholar 

  • Leo S, Gattuso A, Mazza R, Filice M, Cerra MC, Imbrogno S (2019) Cardiac influence of the β3-adrenoceptor in the goldfish (Carassius auratus): a protective role under hypoxia? J Exp Biol in press: jeb.211334

  • Li N-j, Li W, He P, S-q L (2010) Effect of β3-adrenergic agonists on alveolar fluid clearance in hypoxic rat lungs. Chin Med J 123:1028–1033

    CAS  PubMed  Google Scholar 

  • Li B, Qing T, Zhu J, Wen Z, Yu Y, Fukumura R, Zheng Y, Gondo Y, Shi L (2017) A comprehensive mouse transcriptomic BodyMap across 17 tissues by RNA-seq. Sci Rep 7:4200

    PubMed  PubMed Central  Google Scholar 

  • Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, Reuter I, Chekmenev D, Krull M, Hornischer K, Voss N, Stegmaier P, Lewicki-Potapov B, Saxel H, Kel AE, Wingender E (2006) TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes. Nucleic Acids Res 34:D108–D110

    CAS  PubMed  Google Scholar 

  • Messeguer X, Escudero R, Farré D, Núñez O, Martı́nez J, Albà MM (2002) PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 18:333–334

    CAS  PubMed  Google Scholar 

  • Michel MC (2014) Do ß-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder? Naunyn Schmiedebergs Arch Pharmacol 387:215–224

    CAS  PubMed  Google Scholar 

  • Michel MC, Gravas S (2016) Safety and tolerability of ß3-adrenoceptor agonists in the treatment of overactive bladder syndrome - insight from transcriptosome and experimental studies. Expert Opin Drug Safety 15:647–657

    CAS  Google Scholar 

  • Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C, Balligand JL (2001a) Upregulation of ß3-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 103:1649–1655

  • Moniotte S, Vaerman JL, Kockx MM, Larrouy D, Langin D, Noirhomme P, Balligand JL (2001b) Real-time RT-PCR for the detection of beta-adrenoceptor messenger RNAs in small human endomyocardial biopsies. J Mol Cell Cardiol 33:2121–2133

  • Myers DA, Hanson K, Mlynarczyk M, Kaushal KM, Ducsay CA (2008) Long-term hypoxia modulates expression of key genes regulating adipose function in the late-gestation ovine fetus. Am J Phys Regul Integr Comp Phys 294:R1312–R1318

    CAS  Google Scholar 

  • Nahmias C, Blin N, Elalouf JM, Mattei MG, Strosberg AD, Emorine LJ (1991) Molecular characterization of the mouse ß3-adrenergic receptor: relationship with the atypical receptor of adipocytes. EMBO J 10:3721–3727

    CAS  PubMed  PubMed Central  Google Scholar 

  • Najafi M, Farhood B, Mortezaee K (2019) Cancer stem cells (CSCs) in cancer progression and therapy. J Cell Physiol 234:8381–8395

    CAS  PubMed  Google Scholar 

  • Nantel F, Bonin H, Emorine LJ, Zelberfarb V, Strosberg AD, Bouvier M, Marullo S (1993) The human ß3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol Pharmacol 43:548–555

    CAS  PubMed  Google Scholar 

  • Nantel F, Bouvier M, Strosberg AD, Marullo S (1995) Functional effects of long-term activation of human ß2- and ß3-adrenoceptor signalling. Br J Pharmacol 114:1045–1051

    CAS  PubMed  PubMed Central  Google Scholar 

  • Napp A, Brixius K, Pott C, Ziskoven C, Boelck B, Mehlhorn U, Schwinger RHG, Bloch W (2009) Effects of the ß3-adrenergic agonist BRL 37344 on endothelial nitric oxide synthase phosphorylation and force of contraction in human failing myocardium. J Card Fail 15:57–67

  • Okeke K, Angers S, Bouvier M, Michel MC (2019) Agonist-induced desensitisation of β3-adrenoceptors: where, when and how? Br J Pharmacol 176:2539–2558

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ozakca I, Arioglu-Inan E, Esfahani H, Altan VM, Balligand J-L, Kayki-Mutlu G, Ozcelikay AT (2013) Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β1-adrenoceptor blockage. American Journal of Physiology - Heart and Circulatory Physiology 304:H1267–H1276

  • Ratcliffe PJ (2013) Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol 591:2027–2042

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ristori C, Filippi L, Dal Monte M, Martini D, Cammalleri M, Fortunato P, la Marca G, Fiorini P, Bagnoli P (2011) Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of β-adrenoreceptor blockade. Invest Ophthalmol Vis Sci 52:155–170

    CAS  PubMed  Google Scholar 

  • Sun J, Fu L, Tang X, Han Y, Ma D, Cao J, Kang N, Ji H (2011) Testosterone modulation of cardiac ß-adrenergic signals in a rat model of heart failure. Gen Comp Endocrinol 172:518–525

  • Uhlen M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Al-Khalili Szigyarto C, Odeberg J, Djureinovic D, Ottosson Takanen J, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen JJ, Ponten F (2015) Tissue-based map of the human proteome. Science 347:1260419

    PubMed  Google Scholar 

  • Woo AYH, Song Y, Xiao RP, Zhu W (2015) Biased ß2-adrenoceptor signalling in heart failure: pathophysiology and drug discovery. Br J Pharmacol 172:5444–5456

    CAS  PubMed  Google Scholar 

  • Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS, Fong G, Gygi SP, Lefkowitz RJ, Stamler JS (2009) Oxygen-regulated β2-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci Signal 2:ra33–ra33

    PubMed  PubMed Central  Google Scholar 

  • Yoshioka Y, Kadoi H, Yamamuro A, Ishimaru Y, Maeda S (2016) Noradrenaline increases intracellular glutathione in human astrocytoma U-251 MG cells by inducing glutamate-cysteine ligase protein via β3-adrenoceptor stimulation. Eur J Pharmacol 772:51–61

    CAS  PubMed  Google Scholar 

  • Zhao Q, Zeng F, Liu J-B, He Y, Li B, Jiang Z-F, Wu T-G, Wang L-X (2013) Upregulation of β3-adrenergic receptor expression in the atrium of rats with chronic heart failure. J Cardiovasc Pharmacol Ther 18:133–137

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Funding

Work in the authors’ labs was supported in part by grants from the Ankara University (15L0237005, 16L0237006, 17L0237002, 17L0230010 to EAI), Deutsche Forschungsgemeinschaft (Mi 294/10-1 to MCM) and TUBITAK (SBAG-115S564 to EAI).

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Authors and Affiliations

  1. Department of Biology, University of Pisa, Pisa, Italy

    Massimo Dal Monte

  2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Bronwyn A. Evans

  3. Department. of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara, Turkey

    Ebru Arioglu-Inan

  4. Department. of Pharmacology, Johannes Gutenberg University, Mainz, Germany

    Martin C. Michel

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  1. Massimo Dal Monte
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  2. Bronwyn A. Evans
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  3. Ebru Arioglu-Inan
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  4. Martin C. Michel
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Contributions

MDM, EAI, and MCM conceived the project. MDM and EAI performed the literature search for cancer and cardiovascular disease, respectively. BAE performed the gene promoter analysis. MCM drafted the manuscript. All the authors read, critically revised, and approved the manuscript.

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Correspondence to Martin C. Michel.

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MCM is a consultant to Astellas and Velicept related to β3-adrenergic receptors and a shareholder of the latter company. MDM, BAE, and EAI do not report a conflict of interest.

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Dal Monte, M., Evans, B.A., Arioglu-Inan, E. et al. Upregulation of β3-adrenoceptors—a general marker of and protective mechanism against hypoxia?. Naunyn-Schmiedeberg's Arch Pharmacol 393, 141–146 (2020). https://doi.org/10.1007/s00210-019-01780-6

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