Advertisement

Monocyte Modulation by Liposomal Alendronate Improves Cardiac Healing in a Rat Model of Myocardial Infarction

  • Etty Grad
  • Dikla Gutman
  • Mordechai Golomb
  • Roi Efraim
  • Amit Oppenheim
  • Ilan Richter
  • Haim D. Danenberg
  • Gershon GolombEmail author
Article
  • 40 Downloads
Part of the following topical collections:
  1. In Honor of Robert Langer's 70th Birthday

Abstract

The ischemic injury in acute myocardial infarction (AMI) activates the innate immunity response in two consecutive phases. Classical monocytes (CM) accumulate in the inflammatory phase (first 3 days), and non-classical monocytes (NCM) accumulate in the reparatory phase (4–7 days). We hypothesized that inhibition of monocytes at the second phase post-AMI will lead to better healing by reducing myocardial damage and consequently improve heart function. We examined the effect of monocyte modulation on cardiac healing following MI injury in rats by nano-sized alendronate liposomes (LipAln) treatment. Rats were treated with intravenous (IV) LipAln, on days 5, 7, and 9 after ligation of the left anterior descending artery (LAD). Circulating monocyte levels were reduced after the first LipAln injection, and two peripheral blood monocyte subsets, CM and NCM, were sequentially mobilized after MI. Two weeks after MI, a reduction in infarct size was observed and cardiac function was improved in LipAln-treated rats (fractional shortening of 32.2% ± 1.9% and 26.0% ± 1.3%, for LipAln and saline treated rats, respectively, p < 0.05). This improvement was further corroborated by increased cardiac anti-inflammatory cytokine expression and reduced levels of pro-inflammatory cytokines. In conclusion, LipAln treatment during the second phase after MI improves cardiac healing.

Lay Abstract

Myocardial infarction (MI) occurs when coronary blood flow decreases, causing damage to the heart muscle. Consequently, the body sends cells called monocytes/macrophages as part of a reparatory-inflammatory response. We hypothesized that altering a specific step in the inflammatory process, which the heart utilizes to heal itself, could result in improved heart function. Using a unique drug delivery system of nano-sized particles called liposomes, in which a molecule (bisphosphonate) that is toxic to monocytes is embedded, we successfully altered the inflammatory process, in a rat model of MI. resulting in improved heart function.

The novel technology reported in this issue celebrating Robert Langer’s birthday is directly linked to my previous work with Bob. As Bob’s postdoc at MIT (1984–1986), our group developed heart valve anti-calcification implantable drug delivery systems, which contain a bisphosphonate. His guidance and mentorship then, and to this day, are of great importance. I am forever grateful for his continued contribution.

Graphical Abstract

Keywords

Myocardial infarction Drug delivery Liposomes Alendronate Monocytes Cytokines 

Notes

Funding Information

This study was supported in part by Biorest Ltd., Tel Aviv, Israel (GG and HD). GG is grateful to the Woll Sisters and Brothers Chair in Cardiovascular Diseases.

Compliance with Ethical Standards

Conflict of Interest

GG, HD, and IR have a financial stake in Biorest Ltd.; EG, MG, AE, and AO declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

40883_2019_103_MOESM1_ESM.pptx (993 kb)
ESM 1 (PPTX 993 kb)

References

  1. 1.
    Daskalopoulos EP, Hermans KC, Blankesteijn WM. Cardiac (myo)fibroblast: novel strategies for its targeting following myocardial infarction. Curr Pharm Des. 2014;20(12):1987–2002.CrossRefGoogle Scholar
  2. 2.
    Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol. 2015;5(4):1841–75.CrossRefGoogle Scholar
  3. 3.
    Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11:255–65.CrossRefGoogle Scholar
  4. 4.
    Nahrendorf M, Swirski FK. Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J. 2016;37(11):868–72.CrossRefGoogle Scholar
  5. 5.
    Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res. 2016;119(1):91–112.CrossRefGoogle Scholar
  6. 6.
    Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, et al. Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling. J Am Coll Cardiol. 2002;39(2):241–6.CrossRefGoogle Scholar
  7. 7.
    Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol. 2009;54(2):130–8.CrossRefGoogle Scholar
  8. 8.
    Ruparelia N, Godec J, Lee R, Chai JT, Dall'Armellina E, McAndrew D, et al. Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans. Eur Heart J. 2015;36(29):1923–34.CrossRefGoogle Scholar
  9. 9.
    Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.CrossRefGoogle Scholar
  10. 10.
    Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010;121(22):2437–45.CrossRefGoogle Scholar
  11. 11.
    Danenberg HD, Fishbein I, Gao J, Monkkonen J, Reich R, Gati I, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits. Circulation. 2002;106(5):599–605.CrossRefGoogle Scholar
  12. 12.
    Danenberg HD, Golomb G, Groothuis A, Gao J, Epstein H, Swaminathan RV, et al. Liposomal alendronate inhibits systemic innate immunity and reduces in-stent neointimal hyperplasia in rabbits. Circulation. 2003;108(22):2798–804.CrossRefGoogle Scholar
  13. 13.
    Epstein-Barash H, Gutman D, Markovsky E, Mishan-Eisenberg G, Koroukhov N, Szebeni J, et al. Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death. J Control Release. 2010;146(2):182–95.CrossRefGoogle Scholar
  14. 14.
    Gutman D, Golomb G. Liposomal alendronate for the treatment of restenosis. J Control Release. 2012;161(2):619–27.CrossRefGoogle Scholar
  15. 15.
    Grad E, Zolotarevsky K, Danenberg HD, Nordling-David MM, Gutman D, Golomb G. The role of monocyte subpopulations in vascular injury following partial and transient depletion. Drug Deliv Transl Res. 2018;8(4):945–53.CrossRefGoogle Scholar
  16. 16.
    Aizik G, Grad E, Golomb G. Monocyte-mediated drug delivery systems for the treatment of cardiovascular diseases. Drug Deliv Transl Res. 2018;8(4):868–82.CrossRefGoogle Scholar
  17. 17.
    Eriksen EF, Díez-Pérez A, Boonen S. Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone. 2014;58:126–35.CrossRefGoogle Scholar
  18. 18.
    Rogers MJ, Crockett JC, Coxon FP, Monkkonen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011;49(1):34–41.CrossRefGoogle Scholar
  19. 19.
    van Rooijen N, Sanders A, van den Berg TK. Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J Immunol Method. 1996;193(1):93–9.CrossRefGoogle Scholar
  20. 20.
    Danenberg HD, Fishbein I, Epstein H, Waltenberger J, Moerman E, Monkkonen J, et al. Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery. J Cardiovasc Pharmacol. 2003;42(5):671–9.CrossRefGoogle Scholar
  21. 21.
    Epstein H, Berger V, Levi I, Eisenberg G, Koroukhov N, Gao J, et al. Nanosuspensions of alendronate with gallium or gadolinium attenuate neointimal hyperplasia in rats. J Control Release. 2007;117(3):322–32.CrossRefGoogle Scholar
  22. 22.
    Epstein H, Gutman D, Cohen-Sela E, Haber E, Elmalak O, Koroukhov N, et al. Preparation of alendronate liposomes for enhanced stability and bioactivity: in vitro and in vivo characterization. AAPS J. 2008;10(4):505–15.CrossRefGoogle Scholar
  23. 23.
    Banai S, Finkelstein A, Almagor Y, Assali A, Hasin Y, Rosenschein U, et al. Targeted anti-inflammatory systemic therapy for restenosis: the biorest liposomal alendronate with stenting sTudy (BLAST)-a double blind, randomized clinical trial. Am Heart J. 2013;165(2):234–40 e1.CrossRefGoogle Scholar
  24. 24.
    ClinicalTrials.gov. Phase IIb liposomal alendronate study (blade). 2018. https://clinicaltrials.gov/ct2/show/NCT02645799. Accessed Jan 2019.
  25. 25.
    van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol. 2007;170(3):818–29.CrossRefGoogle Scholar
  26. 26.
    Lang JK. Quantitative determination of cholesterol in liposome drug products and raw materials by high-performance liquid chromatography. J Chromatogr. 1990;507:157–63.CrossRefGoogle Scholar
  27. 27.
    Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):358–67.CrossRefGoogle Scholar
  28. 28.
    Takagawa J, Zhang Y, Wong ML, Sievers RE, Kapasi NK, Wang Y, et al. Myocardial infarct size measurement in the mouse chronic infarction model: comparison of area- and length-based approaches. J Appl Physiol (1985). 2007;102(6):2104–11.CrossRefGoogle Scholar
  29. 29.
    Chow A, Stuckey DJ, Kidher E, Rocco M, Jabbour RJ, Mansfield CA, et al. Human induced pluripotent stem cell-derived cardiomyocyte encapsulating bioactive hydrogels improve rat heart function post myocardial infarction. Stem Cell Rep. 2017;9(5):1415–22.CrossRefGoogle Scholar
  30. 30.
    Majmudar MD, Keliher EJ, Heidt T, Leuschner F, Truelove J, Sena BF, et al. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation. 2013;127(20):2038–46.CrossRefGoogle Scholar
  31. 31.
    Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612–6.CrossRefGoogle Scholar
  32. 32.
    Hofmann U, Frantz S. Role of lymphocytes in myocardial injury, healing, and remodeling after myocardial infarction. Circ Res. 2015;116(2):354–67.CrossRefGoogle Scholar
  33. 33.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.CrossRefGoogle Scholar
  34. 34.
    Ziegler-Heitbrock L. Reprint of: monocyte subsets in man and other species. Cell Immunol. 2014;291(1–2):11–5.CrossRefGoogle Scholar
  35. 35.
    Vlacil AK, Schuett J, Schieffer B, Grote K. Variety matters: diverse functions of monocyte subtypes in vascular inflammation and atherogenesis. Vasc Pharmacol. 2019;113:9–19.CrossRefGoogle Scholar
  36. 36.
    Yrlid U, Jenkins CD, MacPherson GG. Relationships between distinct blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under steady-state conditions. J Immunol. 2006;176(7):4155–62.CrossRefGoogle Scholar
  37. 37.
    Leor J, Rozen L, Zuloff-Shani A, Feinberg MS, Amsalem Y, Barbash IM, et al. Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation. 2006;114:I94–100.CrossRefGoogle Scholar
  38. 38.
    Leuschner F, Rauch PJ, Ueno T, Gorbatov R, Marinelli B, Lee WW, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 2012;209(1):123–37.CrossRefGoogle Scholar
  39. 39.
    Shantsila E, Lip GY. Monocytes in acute coronary syndromes. Arterioscler Thromb Vasc Biol. 2009;29(10):1433–8.CrossRefGoogle Scholar
  40. 40.
    Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res. 2012;110(1):159–73.CrossRefGoogle Scholar
  41. 41.
    Chen B, Frangogiannis NG. Immune cells in repair of the infarcted myocardium. Microcirculation. 2017;24:1–10.Google Scholar
  42. 42.
    Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53(1):31–47.CrossRefGoogle Scholar
  43. 43.
    Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112(3):33.CrossRefGoogle Scholar
  44. 44.
    Wan E, Yeap XY, Dehn S, Terry R, Novak M, Zhang S, et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ Res. 2013;113(8):1004–12.CrossRefGoogle Scholar
  45. 45.
    Ryu JC, Davidson BP, Xie A, Qi Y, Zha D, Belcik JT, et al. Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia. Circulation. 2013;127(6):710–9.CrossRefGoogle Scholar
  46. 46.
    Thomas G, Tacke R, Hedrick CC, Hanna RN. Nonclassical patrolling monocyte function in the vasculature. Arterioscler Thromb Vasc Biol. 2015;35(6):1306–16.CrossRefGoogle Scholar
  47. 47.
    Hilgendorf I, Gerhardt LM, Tan TC, Winter C, Holderried TA, Chousterman BG, et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res. 2014;114(10):1611–22.CrossRefGoogle Scholar
  48. 48.
    Frantz S, Hofmann U, Fraccarollo D, Schafer A, Kranepuhl S, Hagedorn I, et al. Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction. FASEB J. 2013;27(3):871–81.CrossRefGoogle Scholar

Copyright information

© The Regenerative Engineering Society 2019

Authors and Affiliations

  • Etty Grad
    • 1
  • Dikla Gutman
    • 1
  • Mordechai Golomb
    • 2
  • Roi Efraim
    • 2
  • Amit Oppenheim
    • 2
  • Ilan Richter
    • 2
  • Haim D. Danenberg
    • 2
  • Gershon Golomb
    • 1
    Email author
  1. 1.Institute for Drug Research, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Cardiovascular Research CenterHadassah-Hebrew University Medical CenterJerusalemIsrael

Personalised recommendations