CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes.
An increased cardiac fatty acid supply and increased sarcolemmal presence of the long-chain fatty acid transporter CD36 are associated with and contribute to impaired cardiac insulin sensitivity and function. In the present study we aimed at preventing the development of insulin resistance and contractile dysfunction in cardiomyocytes by blocking CD36-mediated palmitate uptake. Insulin resistance and contractile dysfunction were induced in primary cardiomyocytes by 48 h incubation in media containing either 100 nM insulin (high insulin; HI) or 200 μM palmitate (high palmitate; HP). Under both culture conditions, insulin-stimulated glucose uptake and Akt phosphorylation were abrogated or markedly reduced. Furthermore, cardiomyocytes cultured in each medium displayed elevated sarcolemmal CD36 content, increased basal palmitate uptake, lipid accumulation and decreased sarcomere shortening. Immunochemical CD36 inhibition enhanced basal glucose uptake and prevented elevated basal palmitate uptake, triacylglycerol accumulation and contractile dysfunction in cardiomyocytes cultured in either medium. Additionally, CD36 inhibition prevented loss of insulin signalling in cells cultured in HP, but not in HI medium. In conclusion, CD36 inhibition prevents lipid accumulation and lipid-induced contractile dysfunction in cardiomyocytes, but probably independently of effects on insulin signalling. Nonetheless, pharmacological CD36 inhibition may be considered as a treatment strategy to counteract impaired functioning of the lipid-loaded heart.
CARIM, Maastricht University, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands. y.angin@maastrichtuniversity.nl
Yeliz
Y
Angin
Laura K M
LK
Steinbusch
Peter J
PJ
Simons
Sabrina
S
Greulich
Nicole T H
NT
Hoebers
Kim
K
Douma
Marc A M J
MA
van Zandvoort
Will A
WA
Coumans
Wino
W
Wijnen
Michaela
M
Diamant
D Margriet
DM
Ouwens
Jan F C
JF
Glatz
Joost J F P
JJ
Luiken
D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012508:Sarcolemma / Q000378:metabolism; D012518:Sarcomeres / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
D018955:CD36 Antigens; C008132:Cd36 protein, rat; D005227:Fatty Acids; D007328:Insulin; D010168:Palmitates; D014280:Triglycerides; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose