Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

α1-Adrenergic receptor mediates adipose-derived stem cell sheet-induced protection against chronic heart failure after myocardial infarction in rats

Hypertension Research volume 45, pages 283–291 (2022)Cite this article

Abstract

Cell-based therapy using adipose-derived stem cells (ADSCs) has emerged as a novel therapeutic approach to treat heart failure after myocardial infarction (MI). The purpose of this study was to determine whether inhibition of α1-adrenergic receptors (α1-ARs) in ADSCs attenuates ADSC sheet-induced improvements in cardiac functions and inhibition of remodeling after MI. ADSCs were isolated from fat tissues of Lewis rats. In in vitro studies using cultured ADSCs, we determined the mRNA levels of vascular endothelial growth factor (VEGF)-A and α1-AR under normoxia or hypoxia and the effects of norepinephrine and an α1-blocker, doxazosin, on the mRNA levels of angiogenic factors. Hypoxia increased α1-AR and VEGF mRNA levels in ADSCs. Norepinephrine further increased VEGF mRNA expression under hypoxia; this effect was abolished by doxazosin. Tube formation of human umbilical vein endothelial cells was promoted by conditioned media of ADSCs treated with the α1 stimulant phenylephrine under hypoxia but not by those of ADSCs pretreated with phenylephrine plus doxazosin. In in vivo studies using rats with MI, transplanted ADSC sheets improved cardiac functions, facilitated neovascularization, and suppressed fibrosis after MI. These effects were abolished by doxazosin treatment. Pathway analysis from RNA sequencing data predicted significant upregulation of α1-AR mRNA expression in transplanted ADSC sheets and the involvement of α1-ARs in angiogenesis through VEGF. In conclusion, doxazosin abolished the beneficial effects of ADSC sheets on rat MI hearts as well as the enhancing effect of norepinephrine on VEGF expression in ADSCs, indicating that ADSC sheets promote angiogenesis and prevent cardiac dysfunction and remodeling after MI via their α1-ARs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hirche H, Franz C, Bös L, Bissig R, Lang R, Schramm M. Myocardial extracellular K+ and H+ increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion in pigs. J Mol Cell Cardiol. 1980;12:579–93.

    Article  CAS  Google Scholar 

  2. Kurz T, Yamada KA, DaTorre SD, Corr PB. Alpha 1–adrenergic system and arrhythmias in ischaemic heart disease. Eur Heart J. 1991;12:88–98.

    Article  Google Scholar 

  3. Gregorini L, Marco J, Palombo C, Kozàkovà M, Anguissola GB, Cassagneau B, et al. Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents. J Am Coll Cardiol. 1998;31:992–1001.

    Article  CAS  Google Scholar 

  4. Gregorini L, Fajadet J, Robert G, Cassagneau B, Bernis M, Marco J. Coronary vasoconstriction after percutaneous transluminal coronary angioplasty is attenuated by antiadrenergic agents. Circulation. 1994;90:895–907.

    Article  CAS  Google Scholar 

  5. Yamamoto K, Kurata Y, Inoue Y, Adachi M, Tsuneto M, Miake J, et al. Pretreatment with an angiotensin II receptor blocker abolished ameliorating actions of adipose-derived stem cell sheets on cardiac dysfunction and remodeling after myocardial infarction. Regen Ther. 2018;9:79–88.

    Article  Google Scholar 

  6. Jiang Q, Ding S, Wu J, Liu X, Wu Z. Norepinephrine stimulates mobilization of endothelial progenitor cells after limb ischemia. PLoS ONE. 2014;9:e101774. https://doi.org/10.1371/journal.pone.0101774.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wu B, Wang L, Yang X, Mao M, Ye C, Liu P, et al. Norepinephrine inhibits mesenchymal stem cell chemotaxis migration by increasing stromal cell-derived factor-1 secretion by vascular endothelial cells via NE/abrd3/JNK pathway. Exp Cell Res. 2016;349:214–20. https://doi.org/10.1016/j.yexcr.2016.09.007.

    Article  CAS  PubMed  Google Scholar 

  8. Candipan RC, Hsiun PT, Pratt R, Cooke JP. Vascular injury augments adrenergic neurotransmission. Circulation. 1994;89:777–84.

    Article  CAS  Google Scholar 

  9. Chalothorn D, Zhang H, Clayton JA, Thomas SA, Faber A. Catecholamine augments collateral vessel growth and angiogenesis in hindlimb ischemia. Am J Physiol Heart Circ Physiol. 2005;289:H947–59.

    Article  CAS  Google Scholar 

  10. Vinci MC, Bellik L, Filippi S, Ledda F, Parenti A. Trophic effects induced by alpha1D-adrenoceptors on endothelial cells are potentiated by hypoxia. Am J Physiol Heart Circ Physiol. 2007;293:H2140–7.

    Article  CAS  Google Scholar 

  11. Kawamura M, Miyagawa S, Miki K, Saito A, Fukushima S, Higuchi T, et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation. 2012;126:S29–37.

    Article  CAS  Google Scholar 

  12. Menasché P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, et al. The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008;117:1189–200.

    Article  Google Scholar 

  13. Bolli R, Tang XL, Sanganalmath SK, Rimoldi O, Mosna F, Abdel-Latif A, et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation. 2013;128:122–31.

    Article  CAS  Google Scholar 

  14. Zhao T, Zhao W, Meng W, Liu C, Chen Y, Gerling IC, et al. VEGF-C/VEGFR-3 pathway promotes myocyte hypertrophy and survival in the infarcted myocardium. Am J Transl Res. 2015;7:697–709.

    PubMed  PubMed Central  Google Scholar 

  15. Rong SL, Wang XL, Zhang CY, Song ZH, Cui LH, He XF, et al. Transplantation of HGF gene-engineered skeletal myoblasts improve infarction recovery in a rat myocardial ischemia model. PLoS ONE. 2017;12:e0175807. https://doi.org/10.1371/journal.pone.0175807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu J, Wu P, Wang Y, Du Y, Nan A, Liu S, et al. Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis. Am J Transl Res. 2016;8:4605–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Terajima Y, Shimizu T, Tsuruyama S, Sekine H, Ishii H, Yamazaki K, et al. Autologous skeletal myoblast sheet therapy for porcine myocardial infarction without increasing risk of arrhythmia. Cell Med. 2013;6:99–109.

    Article  Google Scholar 

  18. Song H, Cha MJ, Song BW, Kim IK, Chang W, Lim S, et al. Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex. Stem Cells. 2010;28:555–63.

    Article  CAS  Google Scholar 

  19. Hamdi H, Planat-Benard V, Bel A, Puymirat E, Geha R, Pidial L, et al. Epicardial adipose stem cell sheets results in greater post-infarction survival than intramyocardial injections. Cardiovasc Res. 2011;91:483–91.

    Article  CAS  Google Scholar 

  20. Patila T, Miyagawa S, Imanishi Y, Fukushima S, Siltanen A, Mervaala E, et al. Comparison of arrhythmogenicity and proinflammatory activity induced by intramyocardial or epicardial myoblast sheet delivery in a rat model of ischemic heart failure. PLoS ONE. 2015;10:e0123963. https://doi.org/10.1371/journal.pone.0123963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Memon IA, Sawa Y, Fukushima N, Matsumiya G, Miyagawa S, Taketani S, et al. Repair of impaired myocardium by means of implantation of engineered autologous myoblast sheets. J Thorac Cardiovasc Surg. 2005;130:1333–41.

    Article  Google Scholar 

  22. Sekiya N, Matsumiya G, Miyagawa S, Saito A, Shimizu T, Okano T, et al. Layered implantation of myoblast sheets attenuates adverse cardiac remodeling of the infarcted heart. J Thorac Cardiovasc Surg. 2009;138:985–93.

    Article  Google Scholar 

  23. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.

    Article  CAS  Google Scholar 

  24. Harada Y, Yamamoto Y, Tsujimoto S, Matsugami H, Yoshida A, Hisatome I. Transplantation of freshly isolated adipose tissue-derived regenerative cells enhances angiogenesis in a murine model of hind limb ischemia. Biomed Res. 2013;34:23–9.

    Article  CAS  Google Scholar 

  25. Miranville A, Heeschen C, Sengenès C, Curat CA, Busse R, Bouloumié A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation. 2004;110:349–55.

    Article  CAS  Google Scholar 

  26. Nakagami H, Maeda K, Morishita R, Iguchi S, Nishikawa T, Takami Y, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol. 2005;25:2542–47.

    Article  CAS  Google Scholar 

  27. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109:1292–8.

    Article  Google Scholar 

  28. Otsuki Y, Nakamura Y, Harada S, Yamamoto Y, Ogino K, Morikawa K, et al. Adipose stem cell sheets improved cardiac function in the rat myocardial infarction, but did not alter cardiac contractile responses to β-adrenergic stimulation. Biomed Res. 2015;36:11–9.

    Article  CAS  Google Scholar 

  29. Shannon R, Chaudhry M. Effect of alpha1-adrenergic receptors in cardiac pathophysiology. Am Heart J. 2006;152:842–50.

    Article  CAS  Google Scholar 

  30. Adachi M, Watanabe M, Kurata Y, Inoue Y, Notsu T, Yamamoto K, et al. β-Adrenergic blocker, carvedilol, abolishes ameliorating actions of adipose-derived stem cell sheets on cardiac dysfunction and remodeling after myocardial infarction. Circ J. 2019;83:2282–91.

    Article  CAS  Google Scholar 

  31. Watanabe M, Horie H, Kurata Y, Inoue Y, Notsu T, Wakimizu T, et al. Esm1 and Stc1 as angiogenic factors responsible for protective actions of adipose-derived stem cell sheets on chronic heart failure after rat myocardial infarction. Circ J. 2021;85:657–66.

    Article  CAS  Google Scholar 

  32. Shibata R, Murohara T. Future of therapeutic angiogenesis using adipose-derived stem cells in the cardiovascular field. Circ J. 2021;85:667–8.

    Article  Google Scholar 

  33. Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol. 2016;17:611–25.

    Article  CAS  Google Scholar 

  34. Eckhart AD, Yang N, Xin X, Faber JE. Characterization of the alpha1B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle. Proc Natl Acad Sci USA. 1997;94:9487–92.

    Article  CAS  Google Scholar 

  35. Semenza GL. Transcriptional regulation by hypoxia-inducible factor 1 molecular mechanisms of oxygen homeostasis. Trends Cardiovasc Med. 1996;6:151–7.

    Article  CAS  Google Scholar 

  36. Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, et al. Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res. 2003;9:4514–21.

    CAS  PubMed  Google Scholar 

  37. Teeters JC, Erami C, Zhang H, Faber JE. Systemic α1A-adrenoceptor antagonist inhibits neointimal growth after balloon injury of rat carotid artery. Am J Physiol Heart Circ Physiol. 2003;284:H385–92.

    Article  CAS  Google Scholar 

  38. Ciccarelli M, Santulli G, Campanile A, Galasso G, Cervèro P, Altobelli GG, et al. Endothelial alpha1-adrenoceptors regulate neo-angiogenesis. Br J Pharmacol. 2008;153:936–46.

    Article  CAS  Google Scholar 

  39. Pan SL, Guh JH, Huang YW, Chern JW, Chou JY, Teng CM. Identification of apoptotic and antiangiogenic activities of terazosin in human prostate cancer and endothelial cells. J Urol. 2003;169:724–9.

    Article  CAS  Google Scholar 

  40. Keledjian K, Garrison JB, Kyprianou N. Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion. J Cell Biochem. 2005;94:374–88.

    Article  CAS  Google Scholar 

  41. Liao C-H, Guh J-H, Chueh S-C, Yu H-J. Anti-angiogenic effects and mechanism of prazosin. Prostate. 2011;71:976–84.

    Article  CAS  Google Scholar 

  42. Mortensen SP, Egginton S, Madsen M, Hansen JB, Munch GDW, Iepsen UW, et al. Alpha adrenergic receptor blockade increases capillarization and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle. Acta Physiol. 2017;221:32–43.

    Article  CAS  Google Scholar 

  43. Tyurin-Kuzmin PA, Fadeeva JI, Kanareikina MA, Kalinina NI, Sysoeva VY, Dyikanov DT, et al. Activation of β-adrenergic receptors is required for elevated α1A-adrenoreceptors expression and signaling in mesenchymal stromal cells. Sci Rep. 2016;6:32835. https://doi.org/10.1038/srep32835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shionoiri H, Yasuda G, Yoshimura H, Umemura S, Miyajima E, Miyakawa T, et al. Antihypertensive effects and pharmacokinetics of single and consecutive administration of doxazosin in patients with mild to moderate essential hypertension. Cardiovasc Pharmacol. 1987;10:90–5.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiovascular Surgery, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan

    Hiromu Horie, Yasushi Yoshikawa & Motonobu Nishimura

  2. Division of Regenerative Medicine and Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan

    Ichiro Hisatome, Yasutaka Yamamoto, Tomomi Notsu, Maaya Adachi, Peili Li, Motokazu Tsuneto & Yasuaki Shirayoshi

  3. Department of Physiology II, Kanazawa Medical University, Uchinada, Japan

    Yasutaka Kurata

  4. Intensive Care Unit and Department of Cardiology, Toranomon Hospital, Tokyo, Japan

    Masanari Kuwabara

  5. Division of Medical Education, Department of Medical Education, Tottori University Faculty of Medicine, Yonago, Japan

    Takuki Sakaguchi

  6. Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Yonago, Japan

    Yoshiharu Kinugasa & Kazuhiro Yamamoto

  7. Department of Pharmacology, Tottori University Faculty of Medicine, Yonago, Japan

    Junichiro Miake

  8. Division of Integrative Physiology, Faculty of Medicine, Tottori University, Yonago, Japan

    Satoshi Koba

  9. Department of Biological Regulation, Tottori University Faculty of Medicine, Yonago, Japan

    Haruaki Ninomiya

  10. Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Suita, Japan

    Shin Ito

  11. Hanwa Daini Senboku Hospital, Sakai, Osaka, Japan

    Masafumi Kitakaze

Authors
  1. Hiromu Horie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ichiro Hisatome
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasutaka Kurata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasutaka Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomomi Notsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maaya Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peili Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masanari Kuwabara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takuki Sakaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshiharu Kinugasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Junichiro Miake
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Satoshi Koba
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Motokazu Tsuneto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yasuaki Shirayoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Haruaki Ninomiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shin Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Masafumi Kitakaze
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kazuhiro Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yasushi Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Motonobu Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasutaka Kurata.

Ethics declarations

Conflict of interest

IH reported receiving lecturer’s fee from Mochida Pharmaceutical Company; Sanwa Kagaku Kenkyusho Co., Ltd.; Teijin Pharma Co., Ltd.; and Fuji Yakuhin Co., Ltd., and research grants from Mochida Pharmaceutical Company; Teijin Pharma; Fuji Yakuhin Co., Ltd.; and Sanwa Kagaku Kenkyusho Co., Ltd.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Horie, H., Hisatome, I., Kurata, Y. et al. α1-Adrenergic receptor mediates adipose-derived stem cell sheet-induced protection against chronic heart failure after myocardial infarction in rats. Hypertens Res 45, 283–291 (2022). https://doi.org/10.1038/s41440-021-00802-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-021-00802-2

Keywords

This article is cited by

Search

Advanced search

Quick links