Upregulation of β3-adrenoceptors—a general marker of and protective mechanism against hypoxia?
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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.
Keywordsβ3-Adrenoceptor Upregulation Hypoxia Cancer Congestive heart failure Diabetes
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.
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).
Compliance with ethical standards
Conflict of interest
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.
- 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 107:452–460PubMedGoogle Scholar
- 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 107:1130–1138Google 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 6:4615–4632PubMedGoogle 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 2018:6816508–6816508Google 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 176:2509–2524PubMedGoogle 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 303:973–978PubMedPubMedCentralGoogle 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 89:599–606Google 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 109:422PubMedGoogle Scholar
- 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–R1382Google 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–e249Google 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.211334Google 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–D110PubMedGoogle 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 15:647–657Google Scholar
- 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–R1318Google 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–H1276PubMedGoogle 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 52:155–170PubMedGoogle Scholar
- 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 347:1260419PubMedGoogle Scholar