Cardiomyocyte lipids impair β-adrenergic receptor function via PKC activation.
Normal hearts have increased contractility in response to catecholamines. Because several lipids activate PKCs, we hypothesized that excess cellular lipids would inhibit cardiomyocyte responsiveness to adrenergic stimuli. Cardiomyocytes treated with saturated free fatty acids, ceramide, and diacylglycerol had reduced cellular cAMP response to isoproterenol. This was associated with increased PKC activation and reduction of β-adrenergic receptor (β-AR) density. Pharmacological and genetic PKC inhibition prevented both palmitate-induced β-AR insensitivity and the accompanying reduction in cell surface β-ARs. Mice with excess lipid uptake due to either cardiac-specific overexpression of anchored lipoprotein lipase, PPARγ, or acyl-CoA synthetase-1 or high-fat diet showed reduced inotropic responsiveness to dobutamine. This was associated with activation of protein kinase C (PKC)α or PKCδ. Thus, several lipids that are increased in the setting of lipotoxicity can produce abnormalities in β-AR responsiveness. This can be attributed to PKC activation and reduced β-AR levels.
Dept. of Medicine, Columbia University, 630 West 168th St., New York, NY 10032, USA. ijg3@columbia.edu
Konstantinos
K
Drosatos
Kalyani G
KG
Bharadwaj
Anastasios
A
Lymperopoulos
Shota
S
Ikeda
Raffay
R
Khan
Yunying
Y
Hu
Rajiv
R
Agarwal
Shuiqing
S
Yu
Hongfeng
H
Jiang
Susan F
SF
Steinberg
William S
WS
Blaner
Walter J
WJ
Koch
Ira J
IJ
Goldberg
D000818:Animals; D015153:Blotting, Western; D002518:Ceramides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D004452:Echocardiography; D004789:Enzyme Activation / Q000502:physiology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D047468:Immunoprecipitation; D008055:Lipids / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D002518:Ceramides; D004041:Dietary Fats; D004075:Diglycerides; D008055:Lipids; D034741:RNA, Small Interfering; D011943:Receptors, Adrenergic, beta; D012313:RNA; D000242:Cyclic AMP; D011493:Protein Kinase C