In previous experiments, we observed signs of
cardiac failure in mice overexpressing
lipoprotein lipase (LPL) under the control of a muscle specific promotor and in
peroxisome proliferators activated receptor alpha (
PPARalpha) knockout mice overexpressing LPL under the control of the same promotor. In our current investigations, we focussed on morphological consequences and changes in
mRNA and
protein expression in hearts from these animals.
mRNA expression was analysed by differential display analysis and Northern blot as well as by
cDNA microarray analysis followed by pathway analysis.
Protein expression was examined using immunoblot and immunohistochemistry.
Fibrosis was determined by chromotrope
aniline blue staining for
collagen. A distinct increase in the expression of
alpha-tubulin mRNA was noted in hearts of all mutant mouse strains compared with the control. This result was paralleled by increased
alpha-tubulin protein expression. Using
cDNA microarray analysis, we detected an activation of apoptosis, in particular an increase of
caspase-3 expression in hearts of mice overexpressing LPL but not in
PPARalpha knockout mice overexpressing LPL. This finding was confirmed immunohistochemically. In addition, we identified a distinct interstitial increase in
collagen and an increase around blood vessels. In our mouse model, we detect
mRNA and
protein changes typical for
cardiomyopathy even before overt clinical signs of
heart failure. In addition, a small but distinct increase in the rate of apoptosis of cardiomyocytes and fibrotic changes contributes to
cardiac failure in mice overexpressing LPL, whereas additional deficiency in
PPARalpha seems to protect hearts from these effects.