Effects of palmitate on Ca(2+) handling in adult control and ob/ob cardiomyocytes: impact of mitochondrial reactive oxygen species.
Obesity and insulin resistance are associated with enhanced fatty acid utilization, which may play a central role in diabetic cardiomyopathy. We now assess the effect of the saturated fatty acid palmitate (1.2 mmol/l) on Ca(2+) handling, cell shortening, and mitochondrial production of reactive oxygen species (ROS) in freshly isolated ventricular cardiomyocytes from normal (wild-type) and obese, insulin-resistant ob/ob mice. Cardiomyocytes were electrically stimulated at 1 Hz, and the signal of fluorescent indicators was measured with confocal microscopy. Palmitate decreased the amplitude of cytosolic Ca(2+) transients (measured with fluo-3), the sarcoplasmic reticulum Ca(2+) load, and cell shortening by approximately 20% in wild-type cardiomyocytes; these decreases were prevented by the general antioxidant N-acetylcysteine. In contrast, palmitate accelerated Ca(2+) transients and increased cell shortening in ob/ob cardiomyocytes. Application of palmitate rapidly dissipated the mitochondrial membrane potential (measured with tetra-methyl rhodamine-ethyl ester) and increased the mitochondrial ROS production (measured with MitoSOX Red) in wild-type but not in ob/ob cardiomyocytes. In conclusion, increased saturated fatty acid levels impair cellular Ca(2+) handling and contraction in a ROS-dependent manner in normal cardiomyocytes. Conversely, high fatty acid levels may be vital to sustain cardiac Ca(2+) handling and contraction in obesity and insulin-resistant conditions.
Fauconnier
Jérémy
J
Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Andersson
Daniel C
DC
Zhang
Shi-Jin
SJ
Lanner
Johanna T
JT
Wibom
Rolf
R
Katz
Abram
A
Bruton
Joseph D
JD
Westerblad
Håkan
H
D000818:Animals; D002118:Calcium / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D020738:Leptin / Q000172:deficiency; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D032342:Muscle Cells / Q000502:physiology*; D019308:Palmitic Acid / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016276:Ventricular Function
D020738:Leptin; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D002118:Calcium