Key result
Overexpression of LPL in mice led to increased apoptosis and fibrosis contributing to cardiac failure, whereas additional deficiency in PPARalpha protected hearts from these effects.
Why the study?
Does LPL overexpression induce apoptosis and fibrosis in a mouse model of metabolic cardiomyopathy, and does PPARalpha deficiency protect against these effects?
Does LPL overexpression induce apoptosis and fibrosis in a mouse model of metabolic cardiomyopathy, and does PPARalpha deficiency protect against these effects?
In a mouse model of metabolic cardiomyopathy, LPL overexpression induces early signs of heart failure including apoptosis and fibrosis, which appear to be attenuated by PPARalpha deficiency.
Hypothesis-generating in murine metabolic cardiomyopathy; leaves open LPL-PPARalpha pathway as human therapeutic target.
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.
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Gürtl et al. (2009) studied Metabolic cardiomyopathy. Lipoprotein lipase (LPL) overexpression vs. Control mice and PPARalpha knockout mice overexpressing LPL was evaluated on Morphological consequences, mRNA and protein expression changes (apoptosis and fibrosis). Overexpression of LPL in mice led to increased apoptosis and fibrosis contributing to cardiac failure, whereas additional deficiency in PPARalpha protected hearts from these effects.
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