Aging impairs the beneficial effect of granulocyte colony-stimulating factor and stem cell factor on post-myocardial infarction remodeling.
Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6- and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit(+) cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.
Lehrke
Stephanie
S
Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mazhari
Ramesh
R
Durand
Daniel J
DJ
Zheng
Meizi
M
Bedja
Djahida
D
Zimmet
Jeffrey M
JM
Schuleri
Karl H
KH
Chi
Andrew S
AS
Gabrielson
Kathleen L
KL
Hare
Joshua M
JM
D000222:Adaptation, Physiological; D000375:Aging; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001772:Blood Cell Count; D001773:Blood Cells / Q000378:metabolism; D015153:Blotting, Western; D004338:Drug Combinations; D004452:Echocardiography; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006321:Heart / Q000503:physiopathology; D006984:Hypertrophy; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D019089:Stem Cell Factor / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
D018952:Antigens, CD34; D004338:Drug Combinations; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit