Abstract
Both bone marrow (BM) and myocardium contain progenitor cells expressing the c-Kit tyrosine kinase. The aims of this study were to determine the effects of c-Kit mutations on: i. myocardial c-Kit+ cells counts and ii. the stability of left ventricular (LV) contractile function and structure during aging. LV structure and contractile function were evaluated (echocardiography) in two groups of Kit mutant (W/Wv and W41/W42) and in wild type (WT) mice at 4 and 12 months of age and the effects of the mutations on LV mass, vascular density and the numbers of proliferating cells were also determined. In 4 month old Kit mutant and WT mice, LV ejection fractions (EF) and LV fractional shortening rates (FS) were comparable. At 12 months of age EF and FS were significantly decreased and LV mass was significantly increased only in W41/W42 mice. Myocardial vascular densities and c-Kit+ cell numbers were significantly reduced in both mutant groups when compared to WT hearts. Replacement of mutant BM with WT BM at 4 months of age did not prevent these abnormalities in either mutant group although they were somewhat attenuated in the W/Wv group. Notably BM transplantation did not prevent the development of cardiomyopathy in 12 month W41/W42 mice. The data suggest that decreased numbers and functional capacities of c-Kit+ cardiac resident progenitor cells may be the basis of the cardiomyopathy in W41/W42 mice and although defects in mutant BM progenitor cells may prove to be contributory, they are not causal.
Highlights
The Kit oncogene (Kit), formerly known as c-Kit or W, codes for the c-Kit receptor
We hypothesized that a cardiomyopathy might develop in c-Kit mutant animals as they aged and we examined the stability of left ventricular (LV) structure and function with echocardiography over the first year of life in several groups of mice with Kit mutations (W/Wv and W41/W42) and in wild type (WT) mice
bone marrow (BM) Transplantation did not increase myocardial cardiac progenitor cells (CPCs) numbers in W41/W42 mice We have previously reported that different type of Kit mutant mice manifested different levels of anemia; importantly, the anemia in all mutant types tested was corrected by transplantation of normal BM following irradiation of the mutant mice [1]
Summary
The Kit oncogene (Kit), formerly known as c-Kit or W, codes for the c-Kit receptor (a tyrosine kinase). Cardiac progenitor cells (CPCs) with functionally competent c-Kit receptors appear to play an important role in maintaining cardiomyocyte replacement; c-Kit+ progenitor cells of BM derivation may be important for the maintenance of cardiac structure and function [8,9,10,11,12,13,14]. It is possible that functionally significant mutations of c-Kit receptors in cardiac and/or BM c-Kit+ cells might reduce the basal rate of cardiomyocyte replacement sufficiently to impact myocardial function and structure as animals age. We hypothesized that a cardiomyopathy might develop in c-Kit mutant animals as they aged and we examined the stability of LV structure and function with echocardiography over the first year of life (i.e., until ,middle age) in several groups of mice with Kit mutations (W/Wv and W41/W42) and in wild type (WT) mice
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