Goran Marinković1, Duco Steven Koenis2, Lisa de Camp3, Robert Jablonowski4, Naomi Graber3, Vivian de Waard2, Carlie Jacoba de Vries2, Isabel Goncalves1,5, Jan Nilsson1, Stefan Jovinge3,6,7, Alexandru Schiopu1,8,9. 1. From the Department of Clinical Sciences Malmö, Lund University, Sweden (G.M., I.G., J.N., A.S.). 2. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, the Netherlands (D.S.K., V.d.W., C.J.d.V.). 3. DeVos Cardiovascular Research Program, Van Andel Institute, Grand Rapids, MI (L.d.C., N.G., S.J.). 4. Department of Clinical Sciences Lund, Lund University, Sweden (R.J.). 5. Department of Cardiology, Skane University Hospital, Sweden (I.G.). 6. DeVos Cardiovascular Research Program, Fredrik Meijer Heart and Vascular Institute, Spectrum Health, Grand Rapids, MI (S.J.). 7. Cardiovascular Institute, Stanford University, CA (S.J.). 8. University of Medicine, Pharmacy, Sciences and Technology of Targu-Mures, Romania (A.S.). 9. Department of Internal Medicine, Skane University Hospital, Sweden (A.S.).
Abstract
RATIONALE: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction. Short-term S100A9 blockade during the inflammatory phase post-myocardial infarction inhibits systemic and cardiac inflammation and improves cardiac function long term. OBJECTIVE: To evaluate the impact of S100A9 blockade on postischemic cardiac repair. METHODS AND RESULTS: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in WT (wild type) C57BL/6 mice with permanent coronary artery ligation, treated with the specific S100A9 blocker ABR-238901 for 7 or 21 days. In contrast to the beneficial effects of short-term therapy, extended S100A9 blockade led to progressive deterioration of cardiac function and left ventricle dilation. The treatment reduced the proliferation of Lin-Sca-1+c-Kit+ hematopoietic stem and progenitor cells in the bone marrow and the production of proreparatory CD150+CD48-CCR2+ hematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6CloMerTKhi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes, and a larger myocardial scar. The transcription factor Nur77 (Nr4a1 [nuclear receptor subfamily 4 group A member 1]) mediates the transition from inflammatory Ly6Chi monocytes to reparatory Ly6Clo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in vitro and in Ly6Chi/int monocytes in vivo, and S100A9 blockade antagonized these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9-/- mice with permanent myocardial ischemia, leading to depressed cardiac function long term. CONCLUSIONS: We show that S100A9 plays an important role in both the inflammatory and the reparatory immune responses to myocardial infarction. Long-term S100A9 blockade negatively impacts cardiac recovery and counterbalances the beneficial effects of short-term therapy. These results define a therapeutic window targeting the inflammatory phase for optimal effects of S100A9 blockade as potential immunomodulatory treatment in acute myocardial infarction.
RATIONALE: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction. Short-term S100A9 blockade during the inflammatory phase post-myocardial infarction inhibits systemic and cardiac inflammation and improves cardiac function long term. OBJECTIVE: To evaluate the impact of S100A9 blockade on postischemic cardiac repair. METHODS AND RESULTS: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in WT (wild type) C57BL/6 mice with permanent coronary artery ligation, treated with the specific S100A9 blocker ABR-238901 for 7 or 21 days. In contrast to the beneficial effects of short-term therapy, extended S100A9 blockade led to progressive deterioration of cardiac function and left ventricle dilation. The treatment reduced the proliferation of Lin-Sca-1+c-Kit+ hematopoietic stem and progenitor cells in the bone marrow and the production of proreparatory CD150+CD48-CCR2+ hematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6CloMerTKhi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes, and a larger myocardial scar. The transcription factor Nur77 (Nr4a1 [nuclear receptor subfamily 4 group A member 1]) mediates the transition from inflammatory Ly6Chi monocytes to reparatory Ly6Clo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in vitro and in Ly6Chi/int monocytes in vivo, and S100A9 blockade antagonized these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9-/- mice with permanent myocardial ischemia, leading to depressed cardiac function long term. CONCLUSIONS: We show that S100A9 plays an important role in both the inflammatory and the reparatory immune responses to myocardial infarction. Long-term S100A9 blockade negatively impacts cardiac recovery and counterbalances the beneficial effects of short-term therapy. These results define a therapeutic window targeting the inflammatory phase for optimal effects of S100A9 blockade as potential immunomodulatory treatment in acute myocardial infarction.
Authors: Lejla Medzikovic; Hylja Heese; Pieter B van Loenen; Cindy P A A van Roomen; Ingeborg B Hooijkaas; Vincent M Christoffels; Esther E Creemers; Carlie J M de Vries; Vivian de Waard Journal: Int J Mol Sci Date: 2021-02-05 Impact factor: 5.923
Authors: Michael J Daseke; Upendra Chalise; Mediha Becirovic-Agic; Jeffrey D Salomon; Leah M Cook; Adam J Case; Merry L Lindsey Journal: Cell Signal Date: 2020-10-24 Impact factor: 4.315