Science China Life Sciences

, Volume 57, Issue 2, pp 201–208 | Cite as

Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

  • YaBin Wang
  • Sai Ma
  • Qiang Wang
  • WenXing Hu
  • DongJuan Wang
  • XiuJuan Li
  • Tao Su
  • Xing Qin
  • XiaoTian Zhang
  • Ke Ma
  • JiangWei Chen
  • LiZe Xiong
  • Feng Cao
Open Access
Research Paper Thematic Issue: Stem cells and regenerative medicine in China

Abstract

Cannabinoid receptor type 2 (CB2) activation is recently reported to promote proliferation of some types of resident stem cells (e.g., hematopoietic stem/progenitor cell or neural progenitor cell). Resident cardiac progenitor cell (CPC) activation and proliferation are crucial for endogenous cardiac regeneration and cardiac repair after myocardial infarction (MI). This study aims to explore the role and possible mechanisms of CB2 receptor activation in enhancing myocardial repair. Our results revealed that CB2 receptor agonist AM1241 can significantly increase CPCs by c-kit and Runx1 staining in ischemic myocardium as well as improve cardiomyocyte proliferation. AM1241 also decreased serum levels of MDA, TNF-α and IL-6 after MI. In addition, AM1241 can ameliorate left ventricular ejection fraction and fractional shortening, and reduce fibrosis. Moreover, AM1241 treatment markedly increased p-Akt and HO-1 expression, and promoted Nrf-2 nuclear translocation. However, PI3K inhibitor wortmannin eliminated these cardioprotective roles of AM1241. In conclusion, AM1241 could induce myocardial regeneration and improve cardiac function, which might be associated with PI3K/Akt/Nrf2 signaling pathway activation. Our findings may provide a promising strategy for cardiac endogenous regeneration after MI.

Keywords

CB2 receptor cardiac progenitor cells endogenous cardiac regeneration 

References

  1. 1.
    Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature, 2001, 410: 701–705PubMedCrossRefGoogle Scholar
  2. 2.
    Wen Z, Mai Z, Zhang H, Chen Y, Geng D, Zhou S, Wang J. Local activation of cardiac stem cells for post-myocardial infarction cardiac repair. J Cell Mol Med, 2012, 16: 2549–2563PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marbán E. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med, 2013, 5: 191–209PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA, 2003, 100: 12313–12318PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Garbern JC, Lee RT. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell, 2013, 12: 689–698PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hajrasouliha AR, Tavakoli S, Ghasemi M, Jabehdar-Maralani P, Sadeghipour H, Ebrahimi F, Dehpour AR. Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur J Pharmacol, 2008, 579: 246–252PubMedCrossRefGoogle Scholar
  7. 7.
    Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach F, Steffens S. CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/ reperfusion. J Mol Cell Cardiol, 2009, 46: 612–620PubMedCrossRefGoogle Scholar
  8. 8.
    Palazuelos J, Ortega Z, Diaz-Alonso J, Guzman M, Galve-Roperh I. CB2 cannabinoid receptors promote neural progenitor cell prolifer- ation via mTORC1 signaling. J Biol Chem, 2012, 287: 1198–1209PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    [Jiang S, Alberich-Jorda M, Zagozdzon R, Parmar K, Fu Y, Mauch P, Banu N, Makriyannis A, Tenen DG, Avraham S, Groopman JE, Avraham HK. Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobiliz- ation. Blood, 2011, 117: 827–838PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Gao E, Lei YH, Shang X, Huang ZM, Zuo L, Boucher M, Fan Q, Chuprun JK, Ma XL, Koch WJ. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res, 2010, 107: 1445–1453PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Duerr GD, Heinemann JC, Dunkel S, Zimmer A, Lutz B, Lerner R, Roell W, Mellert F, Probst C, Esmailzadeh B, Welz A, Dewald O. Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis. Life Sci, 2013, 92: 976–983PubMedCrossRefGoogle Scholar
  12. 12.
    Li Q, Shi M, Li B. Anandamide enhances expression of heat shock protein 72 to protect against ischemia-reperfusion injury in rat heart. J Physiol Sci JPS, 2013, 63: 47–53PubMedCrossRefGoogle Scholar
  13. 13.
    Barana A, Amorós I, Caballero R, Gómez R, Osuna L, Lillo MP, Blázquez C, Guzmán M, Delpón E, Tamargo J. Endocannabinoids and cannabinoid analogues block cardiac hKv1.5 channels in a cannabinoid receptor-independent manner. Cardiovasc Res, 2010, 85: 56–67PubMedCrossRefGoogle Scholar
  14. 14.
    Hiley CR. Endocannabinoids and the heart. J Cardiovasc Pharmacol, 2009, 53: 267–276PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, Nadal-Ginard B, Torella D, Ellison GM. The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. Eur Heart J, 2012, Epub ahead of printGoogle Scholar
  16. 16.
    Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, Smith A, Torella M, Cuellas Ramon C, Gonzalo-Orden JM, Agosti V, Indolfi C, Galiñanes M, Fernandez-Vazquez F, Nadal-Ginard B. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am College Cardiol, 2011, 58: 977–986CrossRefGoogle Scholar
  17. 17.
    Di Nardo P, Forte G, Ahluwalia A, Minieri M. Cardiac progenitor cells: potency and control. J Cell Physiol, 2010, 224: 590–600PubMedCrossRefGoogle Scholar
  18. 18.
    Anedda A, Lopez-Bernardo E, Acosta-Iborra B, Saadeh Suleiman M, Landazuri MO, Cadenas S. The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress. Free Rad Biol Med, 2013, 61C: 395–407CrossRefGoogle Scholar
  19. 19.
    Dreger H, Westphal K, Wilck N, Baumann G, Stangl V, Stangl K, Meiners S. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res, 2010, 85: 395–403PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Authors and Affiliations

  • YaBin Wang
    • 1
  • Sai Ma
    • 1
  • Qiang Wang
    • 2
  • WenXing Hu
    • 1
  • DongJuan Wang
    • 1
  • XiuJuan Li
    • 1
  • Tao Su
    • 1
  • Xing Qin
    • 1
  • XiaoTian Zhang
    • 1
  • Ke Ma
    • 1
  • JiangWei Chen
    • 1
  • LiZe Xiong
    • 2
  • Feng Cao
    • 1
    • 3
  1. 1.Department of Cardiology, Xijing HospitalFourth Military Medical UniversityXi’anChina
  2. 2.Department of Anesthesiology, Xijing HospitalFourth Military Medical UniversityXi’anChina
  3. 3.Department of CardiologyPLA General HospitalBeijingChina

Personalised recommendations