This study aims to investigate the expression of
metalloproteinases (
MMPs) and their tissue inhibitors (TIMPs) in chronic
doxorubicin cardiomyopathy in a rabbit model and to evaluate the effects of bone marrow-derived mesenchymal stem cell (MSC)
transplantation in this disease. Thirty-nine 3-month-old New Zealand rabbits were divided into 4 groups: group 1 (n = 9) was the untreated control. Groups 2-4 were treated with 6 weeks of
doxorubicin (3 mg/kg). Group 2 (n = 6) received no further treatment. In group 3 (n = 9), animals were treated with culture medium (CM) alone. In group 4 (n = 15), autologous MSCs (1.5-2.0 x 10(6)/ml) were injected in the left ventricular (LV) wall. Hearts were stained with HE and
picrosirius red. MMP-1, -2, -3 and -9 and
TIMP-2 and -3 were detected immunohistochemically. The
mRNA levels were determined by real-time polymerase chain reaction. The results confirmed that
doxorubicin treatment resulted in minimal myocardial
fibrosis and showed that expression of
MMPs increased and
TIMP-3 decreased. The injection procedure resulted in increased myocardial
fibrosis in groups 3 and 4. After MSC injection, MMP-1, MMP-2, and
TIMP-3 expression was higher than that in group 2. CM injection led to more
fibrosis, elevated
TIMP-3, but diminished MMP-1 and MMP-2 expression compared with MSC injection. The
mRNA levels of
MMPs and TIMPs were not significantly different among all groups. In conclusion, chronic
doxorubicin cardiomyopathy was characterized by increased
MMP and decreased
TIMP-3 expression. MSCs injection into the LV resulted in marked differences of
collagen content and
MMP/TIMP expression in the whole heart, although significant numbers of living MSCs were not detected after 4 weeks.