Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes.
The energy need of cardiac muscle cells in vivo is largely covered by the oxidation of saturated and mono-unsaturated fatty acids (FA). However, in vitro studies have shown that the saturated FA C16:0 at physiological concentrations exerts detrimental effects on primary cultures of neonatal rat ventricular myocytes by, as yet, unknown mechanisms. To evaluate the noxious effects of FA in more detail, neonatal cardiomyocytes were exposed to saturated (C16:0; C18:0) or mono-unsaturated (C16:1; cis-C18:1; trans-C18:1) FA, or combinations thereof for up to 48 h. FA (0.5 mM) complexed to bovine serum albumin (BSA) (0.15 mM) were added to a glucose-containing defined medium. Irrespective of the length and degree of unsaturation of the aliphatic chain, FA supplied to the cells were readily incorporated in the phospholipid pool. In the presence of mono-unsaturated FA, cardiomyocytes remained healthy and accumulated substantial amounts of triacylglycerol. In contrast, within 24 h after application of the saturated FA C16:0 or C18:0, cells had become irreversibly damaged, as evidenced by the presence of pyknotic nuclei and massive release of the cytosolic markers lactate dehydrogenase (LDH) and fatty acid-binding protein (FABP). Moreover, the occurrence of DNA-laddering indicated that apoptosis was involved. Induction of apoptotic cell death by C16:0 was counteracted by the co-administration of equimolar amounts of cis-C18:1, whereas trans-C18:1 delayed, but did not prevent, loss of cardiomyocyte viability. The present findings suggest that the incorporation of saturated, but not mono-unsaturated, fatty acids induces alterations in the phospholipid membrane, which initiate apoptotic cell death in neonatal cardiomyocytes.
de Vries
J E
JE
Department of Physiology, Cardiovascular Research Institute Maastricht , Maastricht University, The Netherlands.
Vork
M M
MM
Roemen
T H
TH
de Jong
Y F
YF
Cleutjens
J P
JP
van der Vusse
G J
GJ
van Bilsen
M
M
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005947:Glucose; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018996:Myelin P2 Protein / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D014280:Triglycerides / Q000378:metabolism
D002352:Carrier Proteins; D003470:Culture Media; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D014280:Triglycerides; D012710:Serum Albumin, Bovine; D007770:L-Lactate Dehydrogenase; D005947:Glucose