c-kit dysfunction impairs myocardial healing after infarction.
BACKGROUND
We hypothesized that c-kit receptor function in the bone marrow is important for facilitating healing, leading to efficient cardiac repair after myocardial infarction (MI).


RESULTS
We used Kit(W)/Kit(W-v) c-kit mutant mice and their wild-type littermates to assess the importance of c-kit function in cardiac remodeling after coronary ligation. We found that mutant mice developed 1.6-fold greater ventricular dilation (P=0.008) attributable to a 1.3-fold greater infarct expansion by day 14 after MI (P=0.01). The number of proliferating smooth muscle alpha-actin expressing cells was 1.8-fold lower in mutant mice at day 3 (P<0.01), resulting in a 1.6 to 1.8-fold reduction in total regional nonvascular smooth muscle alpha-actin expressing cells by both microscopy and flow cytometry (P<0.001 for both). This decrease was accompanied by a 1.4-fold reduction in the number of CD31 expressing blood vessels (P<0.05). Prior transplantation of wild-type bone marrow cells into mutant mice rescued the efficient establishment of vessel-rich repair tissue by inducing a 1.5-fold increase in nonvascular smooth muscle alpha-actin expressing cells and CD31 expressing blood vessels (P<0.05 for both). The increased recruitment of cells into the infarct region in the chimeric mice was associated with reduced infarct expansion (P<0.03) compared to wild-type levels.


CONCLUSIONS
Bone marrow c-kit function critically impacts the myofibroblast repair response in infarcted hearts. Interventions that increase the infiltration of c-kit+ cells to the infarcted heart may potentiate this endogenous repair response, prevent infarct expansion, and improve the recovery of cardiac function after MI.
Cimini
Massimo
M
Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, University of Toronto, Ontario, Canada.
Fazel
Shafie
S
Zhuo
Sun
S
Xaymardan
Munira
M
Fujii
Hiroko
H
Weisel
Richard D
RD
Li
Ren-Ke
RK
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D005260:Female; D051379:Mice; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*
D019009:Proto-Oncogene Proteins c-kit