J Physiol Volume 582, Number 1, 349-358, July 1, 2007 DOI: 10.1113/jphysiol.2007.132753
Protein kinase A is activated by the n–3 polyunsaturated fatty acid eicosapentaenoic acid in rat ventricular muscle
Norbert Szentandrássy1,
M. R. Pérez-Bido2,
E. Alonzo3,
N. Negretti2 and
Stephen C. O'Neill1
1 Department of Medicine, University of Manchester, Core Technology Facility, Grafton Street, Manchester M13 9NT, UK
2 Inst. de Medicina Experimental, Facultad de Medicina, University Central de Venezuela, Caracas, Ap. 50587 Venezuela
3 Centro Nacional de Diálisis y Transplante Renal, Hospital Universitario de Caracas, Venezuela
During cardiac ischaemia antiarrhythmic n–3 polyunsaturated fatty acids (PUFAs) are released following activation of phospholipase A2, if they are in the diet prior to ischaemia. Here we show a positive lusitropic effect of one such PUFA, eicosapentaenoic acid (EPA) in the antiarrhythmic concentration range in Langendorff hearts and isolated rat ventricular myocytes due to activation of protein kinase A (PKA). Several different approaches indicated activation of PKA by EPA (5–10 µmol l–1): the time constant of decay of the systolic Ca2+ transient decreased to 65.3 ± 5.0% of control, Western blot analysis showed a fourfold increase in phospholamban phosphorylation, and PKA activity increased by 21.0 ± 7.3%. In addition myofilament Ca2+ sensitivity was reduced in EPA; this too may have resulted from PKA activation. We also found that EPA inhibited L-type Ca2+ current by 38.7 ± 3.9% but this increased to 63.3 ± 3.4% in 10 µmol l–1 H89 (to inhibit PKA), providing further evidence of activation of PKA by EPA. PKA inhibition also prevented the lusitropic effect of EPA on the systolic Ca2+ transient and contraction. Our measurements show, however, PKA activation in EPA cannot be explained by increased cAMP levels and alternative mechanisms for PKA activation are discussed. The combined lusitropic effect and inhibition of contraction by EPA may, respectively, combat diastolic dysfunction in ischaemic cardiac muscle and promote cell survival by preserving ATP. This is a further level of protection for the heart in addition to the well-documented antiarrhythmic qualities of these fatty acids.
(Received 19 March 2007;
accepted after revision 10 May 2007;
first published online 17 May 2007)
Corresponding author S. C. O'Neill: Department of Medicine, University of Manchester, Core Technology Facility, Grafton Street, Manchester M13 9PT, UK. Email: mdssssco{at}manchester.ac.uk
Copyright © 2007 The Physiological Society.
