Abstract 18751: c-Kit+ Resident Cardiac Progenitor Cells Proliferate and Form New Myocytes Following Catecholamine Induced Cardiac Injury
Chronic catecholamine (CAT) infusion causes cardiac injury with reactive myocyte hypertrophy and fibrosis. We tested the hypothesis that CAT injury induces cardiac repair by activating both resident cardiac and blood derived progenitor cells.
Methods: Cardiomyopathy was induced in adult felines by infusion of L-isoproterenol (ISO; 1100 ug/kg/hr) from Alzet minipumps for 10 days. Cardiac tissue sections from control, injury (Day 10), early recovery (Day 17), and late recovery (Day 38) were analyzed for c-kit (CD117), a marker expressed on cardiac progenitor cells and some hematopoietic stem cells, and CD45, expressed on cells of hematopoietic origin. Bromodeoxyuridine (BrdU; to identify proliferative cells) was infused via minipumps (50 mg/ml) either 7 days prior to euthanasia or during ISO injury (pulse) with animals examined after some recovery (Day 38; chase).
Results: ISO treatment was associated with a significant increase (6-fold) in the percent of c-kit+BrdU+ nuclei at Day 10 (0.072 ± 0.01%, p<0.001) compared with control (0.012 ± 0.003%), with a much smaller increase (2-fold) in the percent of CD45+BrdU+ nuclei at Day 10 (0.019 ± 0.002%, p<0.01) compared with control (0.008 ± 0.002%). There was also a significant increase in the ratio of c-kit+BrdU+ to c-kit+ nuclei (5-fold) at Day 10 (0.369 ± 0.048, p<0.001) compared with control (0.067 ± 0.015). Since 51% of c-kit+ cells were CD45 negative at Day 10, and only 24% of cells were solely CD45+ relative to c-kit+ and c-kit+CD45+ cells, these results indicate a more active proliferative response by resident c-kit+ progenitor cells following injury. In the left atrium (LA) of animals in which BrdU minipumps were implanted during the ISO injury phase and then removed at Day 10, with hearts explanted at Day 38, the percent of c-kit+BrdU+ LA nuclei (0.043 ± 0.006%, p<0.001) and the ratio of c-kit+BrdU+ to c-kit+ nuclei (0.162 ± 0.022, p<0.05) was significantly greater than in controls, indicating continued proliferative capacity. This activity was associated with an increase in BrdU+ LA myocyte nuclei (2.045 ± 0.746%, p<0.01), significantly greater than in controls.
Conclusion: CAT injury induces proliferation of resident c-kit+ cardiac progenitors and these cells differentiate into new cardiac myocytes.
- © 2010 by American Heart Association, Inc.