The Role of myelopoiesis in myocardial infarction and atherosclerosis

Myocardial infarction increases inflammation in atherosclerotic plaques. Increased inflammation in the aortic root measure by FMT-CT imaging (Dutta et al., Nature, 2012)

We found that acute myocardial infarction activation the sympathetic system in the bone marrow, resulting in hematopoietic stem cell mobilization to extramedullary sites. This accelerates ongoing atherosclerosis, which may trigger a second heart attack. We demonstrated that atherosclerotic plaques become more vulnerable after myocardial infarction. Not only myocardial infarction but also stroke exacerbates ongoing atherosclerosis by increasing sympathetic tone. We also found that accumulation and proliferation of hematopoietic stem and progenitor cells in the spleen give rise to inflammatory monocytes that are responsible for worsening atherosclerosis. This can be blocked with chemical sympathetic ablation and a selective beta 3 antagonist resulting in less inflamed atherosclerotic plaques, thereby reducing chances of a second heart attack. This body of work discovered several therapeutic targets to reduce hostile inflammation in cardiovascular disease.

Selected Publications

Leuschner, F*., Dutta, P.*, Gorbatov, R., Novobrantseva, T. I., Donahoe, J. S., Courties, G., Lee, K. M., Kim, J. I., Markmann, J. F., Marinelli, B., Panizzi, P., Lee, W. W., Iwamoto, Y., Milstein, S., Epstein-Barash, H., Cantley, W., Wong, J., Cortez-Retamozo, V., Newton, A., Love, K., Libby, P., Pittet, M. J., Swirski, F. K., Koteliansky, V., Langer, R., Weissleder, R., Anderson, D. G. and Nahrendorf, M. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature Biotechnology 29: 1005-1010. PMCID: PMC3212614 *Equal contribution authors

Dutta, P., Courties, G., Wei, Y., Leuschner, F., Gorbatov, R., Robbins, C. S., Iwamoto, Y., Thompson, B., Carlson, A. L., Heidt, T., Majmudar, M. D., Lasitschka, F., Etzrodt, M., Waterman, P., Waring, M. T., Chicoine, A. T., van der Laan, A. M., Niessen, H. W., Piek, J. J., Rubin, B. B., Butany, J., Stone, J. R., Katus, H. A., Murphy, S. A., Morrow, D. A., Sabatine, M. S., Vinegoni, C., Moskowitz, M. A., Pittet, M. J., Libby, P., Lin, C. P., Swirski, F. K., Weissleder, R. and Nahrendorf, M. Myocardial infarction accelerates atherosclerosis. Nature 487: 325-329. PMCID: PMC3401326

Sager HB*, Dutta P*, Dahlman JE, Borodovsky A, Fitzgerald K, Heidt T, Courties G, Wojtkiewicz GR, Iwamoto Y, Sebas M, Khan OF, Xing Y, Shaw TE, Libby P, Swirski FK, Langer R, Weissleder R, Anderson DG, Nahrendorf. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Science Translational Medicine 2016. 8: 342ra80. PMCID: PMC5125383 * Equal contribution authors

Dutta P, Hoyer FF, Sun Y, Iwamoto Y, Tricot B, Weissleder R, Magnani JL, Swirski FK, Nahrendorf M. E-selectin inhibition mitigates splenic HSC activation and myelopoiesis in hypercholesterolemic mice with myocardial infarction. Atheroscler Thromb Vasc Biol 36: 1802-8. PMCID: PMC5001901