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Effects of Palmitate on Ca²⁺ Handling in Adult Control and ob/ob Cardiomyocytes

Impact of Mitochondrial Reactive Oxygen Species

¹ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
² Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

Address correspondence and reprint requests to Håkan Westerblad, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. E-mail: hakan.westerblad{at}ki.se

Abbreviations: ECC, excitation-contraction coupling; FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; NAC, N-acetylcysteine; ROS, reactive oxygen species; SOD, superoxide dismutase; SR, sarcoplasmic reticulum; TMRE, tetra-methyl rhodamine-ethyl ester

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 Ca²⁺ 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 Ca²⁺ transients (measured with fluo-3), the sarcoplasmic reticulum Ca²⁺ load, and cell shortening by 20% in wild-type cardiomyocytes; these decreases were prevented by the general antioxidant N-acetylcysteine. In contrast, palmitate accelerated Ca²⁺ 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 Ca²⁺ handling and contraction in a ROS-dependent manner in normal cardiomyocytes. Conversely, high fatty acid levels may be vital to sustain cardiac Ca²⁺ handling and contraction in obesity and insulin-resistant conditions.

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