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.

非酯化脂肪酸（nonesterified fatty acids）会在组织损伤与坏死部位蓄积。在心肌组织中，由于磷脂酶（phospholipases）经受体或非受体介导激活，且再酰化（reacylation）过程减弱，缺血（ischemia）期间油酸（oleic acid）、花生四烯酸（arachidonic acid）、白三烯（leukotrienes）及其他脂肪酸的浓度会显著升高。在缺血心肌（ischemic myocardium）中，脂肪酸与组织钙水平的升高时间进程与不可逆心肌损伤高度同步。我们提出假说：从膜磷脂中释放的脂肪酸可能参与了细胞内钙（intracellular calcium）水平的升高。
本文报道，低浓度（3~30 μM）的各类长链不饱和脂肪酸（long-chain unsaturated fatty acids，包括油酸、亚油酸（linoleic acid）、亚麻酸（linolenic acid）与花生四烯酸）及饱和脂肪酸（saturated fatty acids，包括棕榈酸（palmitic acid）、硬脂酸（stearic acid）与花生酸（arachidic acid））均可使心肌细胞（cardiac myocytes）的电压依赖性钙电流（voltage-dependent calcium currents，ICa）出现数倍增幅。与之相反，短链脂肪酸（short-chain fatty acids，碳链长度小于12）或脂肪酸酯（fatty acid esters，油酸甲酯与棕榈酸甲酯）均未对ICa产生任何影响，这表明钙通道的激活依赖于脂肪酸的碳链长度，且必须带有游离羧基（free carboxyl group）。
抑制蛋白激酶C与A（protein kinases C and A）、G蛋白（G proteins）、类花生酸生成（eicosanoid production）或非酶促氧化（nonenzymatic oxidation），均无法阻断脂肪酸诱导的ICa升高。由此可见，长链脂肪酸似乎可直接激活ICa，其机制可能是作用于钙通道附近的特定脂质位点，或是直接作用于通道蛋白本身。
我们认为，缺血期间释放的脂肪酸对ICa的联合效应，可能参与缺血诱导的心脏钙相关病理性事件，包括心律失常（arrhythmias）、传导紊乱（conduction disturbances）以及细胞毒性钙超载（cytotoxic calcium overload）介导的心肌损伤。