Long-chain fatty acids activate calcium channels in ventricular myocytes.
Nonesterified fatty acids accumulate at sites of tissue injury and necrosis. In cardiac tissue the concentrations of oleic acid, arachidonic acid, leukotrienes, and other fatty acids increase greatly during ischemia due to receptor or nonreceptor-mediated activation of phospholipases and/or diminished reacylation. In ischemic myocardium, the time course of increase in fatty acids and tissue calcium closely parallels irreversible cardiac damage. We postulated that fatty acids released from membrane phospholipids may be involved in the increase of intracellular calcium. We report here that low concentrations (3-30 microM) of each long-chain unsaturated (oleic, linoleic, linolenic, and arachidonic) and saturated (palmitic, stearic, and arachidic) fatty acid tested induced multifold increases in voltage-dependent calcium currents (ICa) in cardiac myocytes. In contrast, neither short-chain fatty acids (less than 12 carbons) or fatty acid esters (oleic and palmitic methyl esters) had any effect on ICa, indicating that activation of calcium channels depended on chain length and required a free carboxyl group. Inhibition of protein kinases C and A, G proteins, eicosanoid production, or nonenzymatic oxidation did not block the fatty acid-induced increase in ICa. Thus, long-chain fatty acids appear to directly activate ICa, possibly by acting at some lipid sites near the channels or directly on the channel protein itself. We suggest that the combined effects of fatty acids released during ischemia on ICa may contribute to ischemia-induced pathogenic events on the heart that involve calcium, such as arrhythmias, conduction disturbances, and myocardial damage due to cytotoxic calcium overload.
Huang
J M
JM
Department of Physiology, University of Minnesota, Minneapolis 55455.
Xian
H
H
Bacaner
M
M
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D004553:Electric Conductivity; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D013329:Structure-Activity Relationship; D013997:Time Factors
D015220:Calcium Channels; D005227:Fatty Acids; D047428:Protein Kinase Inhibitors; D016718:Arachidonic Acid; D011493:Protein Kinase C; D019204:GTP-Binding Proteins