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Fatty acid augmentation of the cardiac slowly activating delayed rectifier current (I_Ks) is conferred by hminK¹

Department of Physiology, The University of Melbourne, Victoria, 3010, Australia

²Correspondence: Department of Physiology, The University of Melbourne, Victoria, 3010, Australia. E-mail: spetrou{at}unimelb.edu.au

SPECIFIC AIMS

In this study, we test the hypothesis that cardioprotective fatty acids, such as the omega-3 polyunsaturated fatty acid and docosahexaenoic acid (DHA), should potentiate the function of the native human I_Ks cardiac current and examine the role of the hminK subunit on the sensitivity of I_Ks to fatty acids.

PRINCIPAL FINDINGS

1. The omega-3 polyunsaturated fatty acid DHA and the fully saturated lauric acid significantly augmented I_K

2. The hminK accessory protein conferred fatty acid sensitivity to I_Ks

3. The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) had no effect on I_Ks

CONCLUSIONS AND SIGNIFICANCE

The native I_Ks cardiac ion channel is fatty acid sensitive
The findings of this study clearly demonstrate that the native I_Ks cardiac current is sensitive to DHA (Fig. 1 A). This result provides an additional molecular mechanism for the antiarrhythmic effects of DHA, an omega-3 polyunsaturated fatty acid reportedly antiarrhythmic in cardiac myocyte, animal, and human studies. It was found that a 20 µM DHA solution significantly augmented I_Ks across a range of potentials. At +40 mV, the current was augmented by > 30%.

View larger version (25K): [in this window] [in a new window]   Figure 1. Lauric acid increases IKs (IKvLQT1+hminK) current (principal finding 1) but not IKvLQT1 current (principal finding 2). A) Current traces from an oocyte injected with both hminK and KVLQT1 cRNA before (left) and after (right) a 60 s exposure to 20 µM lauric acid. B) Current traces from an oocyte injected with KVLQT1 cRNA before (left) and after (right) a 2 min exposure to 20 mM lauric acid. In each case, the voltage was stepped from -80 mV to +40 mV in 10 mV increments. A similar result was found for the omega-3 polyunsaturated fatty acid DHA (principal finding 1).

It is well known that dietary DHA confers protection against fatal arrhythmias, but an explanation for the underlying mechanism of this protection has been elusive. The predominant ionic mechanism invoked is that cardiac Na⁺ channels are inhibited by DHA, thereby reducing the occurrence of early-after depolarizations. Fatty acids have also been shown to block sodium currents in adult rat cardiocytes and Kv_4.3, which encodes a portion of the transient outward current. Furthermore, fatty acids were found to modulate the function of voltage-gated L-type Ca²⁺ currents in rat myocytes. Such modulation over a range of channels hints at the complexity of the actual mechanism of fatty acid antiarrhythmicity.

The long QT syndrome shows that delayed cardiac repolarization leads to increased arrhythmic susceptibility. In certain cases of long QT syndrome, delayed repolarization is the result of mutations in I_Ks proteins that carry the I_Ks current. These mutations reduce the current of I_Ks, delay repolarization and increase the susceptibility to arrhythmias. The present study found that DHA has effects opposite those of long QT mutations, actually enhancing the current of I_Ks. The fact that the DHA modulation of I_Ks occurred over a range of physiologically relevant voltages allows extrapolation to the possible effects of DHA on the cardiac action potential. DHA would have the opposite effect on the cardiac action potential to that of the action of mutations in long QT syndrome. The DHA-elicited increased I_Ks should reduce cardiac repolarization time, thereby reducing the incidence of cardiac arrhythmias. This result is consistent with dietary studies that show that diets high in omega-3 polyunsaturated fatty acids reduce arrhythmic episodes and with acute studies that have documented the antiarrhythmic properties of omega-3 polyunsaturated fatty acids.

Lauric acid was also found to augment the function of I_Ks (Fig. 1A ), as was oleic acid. Considering the fully saturated acyl chain of lauric acid, this augmentation was somewhat surprising. Since saturated fatty acids have been shown to be arrhythmogenic, it was hypothesized that lauric acid would reduce the function of the native I_Ks in much the same way that mutations do in the long QT syndrome and that this action would explain the deleterious effects of saturated fatty acids described in dietary and acute studies. Nevertheless, lauric acid augmented I_Ks by > 30% at +40 mV, again alluding to the complex nature of the mechanisms by which arrhythmias may be enhanced or inhibited.

The antiarrhythmic omega-3 polyunsaturated fatty acid EPA was without effect on I_Ks. Similarly, myristic acid did not modulate the function of I_Ks. This is not to say that EPA, myristic acid, or oleic acid do not modulate other cardiac ion channels to influence the occurrence of arrhythmias. A number of other targets may be modulated to account for the detrimental effects of saturated fatty acids and the beneficial effects of polyunsaturated fatty acids. These may include other members of the long QT family—I_Kr and I_Na—or possibly other cardiac ion channels, including Kv_1.2, Kv_1.5, or Kv_4.3, which was recently found to be blocked by omega-3 polyunsaturated fatty acids. Further investigation is required to fully answer this question.

hminK accessory protein confers fatty acid sensitivity to IKs
The native I_Ks channel is comprised of two proteins: KvLQT1 and the accessory protein hminK. hminK has been shown to confer a number of pharmacological properties to other ion channels. The present study aimed to determine whether the hminK protein may confer fatty acid sensitivity to the KvLQT1 protein as the implications of such a finding would certainly be exciting and of widespread significance to cardiac function. The native I_Ks conducted by the KvLQT1-hminK coassembly was indeed found to be highly sensitive to DHA and lauric acid, both producing significant increases in I_Ks current (Fig. 1A ). In contrast, DHA slightly decreased the current of oocytes injected with KVLQT1 alone, whereas lauric acid had no affect on the KVLQT1 current (Fig. 1B ). These results suggest that the hminK accessory protein confers the enhanced fatty acid sensitivity, including the antiarrhythmic effects of DHA sensitivity to the I_Ks ion channel complex.

The hminK accessory protein is found within a broad range of ion channels, including those in kidney, heart, and brain. Recently, hminK was shown to affect the response of I_Ks to internal pH, actually reversing the pH regulation from inhibition to activation at low pH values. In addition, hminK altered the pharmacological properties and sensitivity to temperature of KvLQT1. Moreover, coexpression studies of other cardiac ion channels have shown that certain subunits can have profound effects on the function of an ion channel. Such has been shown for I_Na, where the functional association of the ß subunit with the subunit modifies the kinetics of the channel as well as its inhibition by fatty acids.

Our finding that hminK confers fatty acid sensitivity to I_Ks has several implications. First, it suggests that the free fatty acid sensitivity of I_Ks may be directly involved with a binding site situated on the hminK protein itself, perhaps similar to those fatty acid binding sites previously described. Such a site would provide a potential target for future therapeutic antiarrhythmic interventions. Some current antiarrhythmic therapies have actually been shown to increase, rather than decrease, death rates in patients, so the development of new and more effective therapies is of great importance. Identification of the site of fatty acid–protein interaction would provide important information that could be used to identify similar sites in other ion channel proteins. Furthermore, the hminK protein has been found to associate with many other ion channel proteins in regions such as the brain and the kidney. It would be interesting to determine whether hminK confers fatty acid sensitivity to these complexes and to ascertain the attendant physiological and pathophysiological consequences of such modulation.

View larger version (19K): [in this window] [in a new window]   Figure 2. Schematic diagram. Summary of the effects of various fatty acids on IKs and IKvLQT1.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0084fje; to cite this article, use FASEB J. (August 19, 2002) 10.1096/fj.02-0084fje

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