Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Nöhammer, C; Brunner, F; Wölkart, G; Staber, PB; Steyrer, E; Gonzalez, FJ; Zechner, R; Hoefler, G.
Myocardial dysfunction and male mortality in peroxisome proliferator-activated receptor alpha knockout mice overexpressing lipoprotein lipase in muscle.
Lab Invest. 2003; 83(2):259-269
Doi: 10.1097/01.LAB.0000053916.61772.CA
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- Führende Autor*innen der Med Uni Graz
- Steyrer Ernst
- Co-Autor*innen der Med Uni Graz
- Höfler Gerald
- Staber Philipp
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- Abstract:
- Free fatty acids (FFA) are liberated from triglyceride-rich lipoproteins by lipoprotein lipase (LPL) and are considered to be a principal energy source for the heart. The peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of FFA catabolism. To investigate its role in cardiac muscle metabolism, transgenic mice overexpressing LPL in skeletal and cardiac muscle were bred on a PPARalpha knockout background. Fifty-five percent of male animals lacking PPARalpha and overexpressing LPL died within 4 months after birth. In contrast, females of this genotype stayed alive. Deceased animals exhibited cardiopulmonary congestion but had no increase of neutral lipids in the heart. Changes in plasma glucose, FFA, lactate, and triglycerides did not clearly account for gender-specific differences in mortality; however, they indicated a critical role for PPARalpha during fasting. Analysis of cardiac function revealed that in isolated perfused hearts, left ventricular developed pressure (a measure of contractility) was markedly lower in PPARalpha knockout mice overexpressing LPL compared with controls. Glucose uptake of isolated perfused hearts was significantly higher in PPARalpha knockout mice with both normal or increased LPL expression. However, uptake of FFA was not different among genotypes. In contrast, fasted FFA levels were significantly lower in cardiac muscle of PPARalpha knockout mice with normal LPL expression (-26%) and PPARalpha knockout mice overexpressing LPL (-38%) compared with controls. Our results indicate a critical role for PPARalpha in myocardial pump function and suggest that mouse models combining different genetic effects such as PPARalpha knockout mice overexpressing muscle LPL may be useful to study cardiomyopathies.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Body Weight -
- Cardiomyopathies - enzymology Cardiomyopathies - genetics Cardiomyopathies - mortality Cardiomyopathies - pathology
- Dose-Response Relationship, Drug -
- Female -
- Humans -
- Lipoprotein Lipase - metabolism
- Longevity -
- Male -
- Mice -
- Mice, Knockout - genetics
- Muscle Contraction - drug effects Muscle Contraction - physiology
- Muscle, Skeletal - enzymology
- Myocardium - enzymology
- Nordefrin - pharmacology
- Perfusion -
- Receptors, Cytoplasmic and Nuclear - genetics
- Sex Factors -
- Strophanthins - pharmacology
- Survival Rate -
- Transcription Factors - genetics
- Ventricular Function, Left - drug effects Ventricular Function, Left - physiology