TY - JOUR
T1 - Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart
AU - Yu, Xinxin
AU - Burgess, Shawn C.
AU - Ge, Hongfei
AU - Wong, Kenny K.
AU - Nassem, R. Haris
AU - Garry, Daniel J.
AU - Sherry, A. Dean
AU - Malloy, Craig R.
AU - Berger, Joel P.
AU - Li, Cai
PY - 2005/2/1
Y1 - 2005/2/1
N2 - To investigate the role of Angptl4, an inhibitor of lipoprotein lipase that is induced by >3-fold in the heart after rosiglitazone treatment, we generated transgenic mice that overexpress Angptl4 in the heart (MHC-Angptl4). We show that MHC-Angptl4 mice exhibit cardiac-restricted expression of the transgene and inhibition of cardiac lipoprotein lipase (LPL) activity. However, LPL activities in other tissues or that released into plasma by heparin are not affected. In addition, MHC-Angptl4 mice also exhibit hypertriglyceridemia after 6 h of fasting. We use echocardiography to show that MHC-Angptl4 mice develop left-ventricular dysfunction. Comparison of the metabolic profiles of isolated working hearts demonstrates that cardiac impairment in MHC-Angptl4 mice is positively associated with decreased triglyceride (TG) utilization. When bred to transgenic mice that overexpress acyl-CoA synthetase in the heart, a strain that exhibits elevated cardiac TG accumulation, cardiac TG content in double transgenic mice is reversed to that of wild-type mice. Taken together, our data support the hypothesis that induction of Angptl4 in the heart inhibits lipoprotein-derived fatty acid delivery. This mouse model will be useful to elucidate the role of reduced fatty acid supply in the pathogenesis of heart failure and related disorders.
AB - To investigate the role of Angptl4, an inhibitor of lipoprotein lipase that is induced by >3-fold in the heart after rosiglitazone treatment, we generated transgenic mice that overexpress Angptl4 in the heart (MHC-Angptl4). We show that MHC-Angptl4 mice exhibit cardiac-restricted expression of the transgene and inhibition of cardiac lipoprotein lipase (LPL) activity. However, LPL activities in other tissues or that released into plasma by heparin are not affected. In addition, MHC-Angptl4 mice also exhibit hypertriglyceridemia after 6 h of fasting. We use echocardiography to show that MHC-Angptl4 mice develop left-ventricular dysfunction. Comparison of the metabolic profiles of isolated working hearts demonstrates that cardiac impairment in MHC-Angptl4 mice is positively associated with decreased triglyceride (TG) utilization. When bred to transgenic mice that overexpress acyl-CoA synthetase in the heart, a strain that exhibits elevated cardiac TG accumulation, cardiac TG content in double transgenic mice is reversed to that of wild-type mice. Taken together, our data support the hypothesis that induction of Angptl4 in the heart inhibits lipoprotein-derived fatty acid delivery. This mouse model will be useful to elucidate the role of reduced fatty acid supply in the pathogenesis of heart failure and related disorders.
KW - Cardiomyopathy
KW - Lipase
KW - Nuclear receptor
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U2 - 10.1073/pnas.0409564102
DO - 10.1073/pnas.0409564102
M3 - Article
C2 - 15659544
AN - SCOPUS:13444250891
SN - 0027-8424
VL - 102
SP - 1767
EP - 1772
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -