Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents

Abstract

There is considerable evidence to support a role for lipotoxicity in the development of diabetic cardiomyopathy, although the molecular links between enhanced saturated fatty acid uptake/ metabolism and impaired cardiac function are poorly understood. In the present study, the effects of acute exposure to the saturated fatty acid, palmitate, on myocardial contractility and excitability were examined directly. Exposure of isolated (adult mouse) ventricular myocytes to palmitate, complexed to bovine serum albumin (palmitate:BSA) as in blood, rapidly reduced (by 54±4%) mean (± SEM) unloaded fractional cell shortening. The amplitudes of intracellular Ca 2+ transients decreased in parallel. Current-clamp recordings revealed that exposure to palmitate:BSA markedly shortened action potential durations at 20, 50 and 90% repolarization. These effects were reversible and were occluded when the K + in the recording pipettes was replaced with Cs + , suggesting a direct effect on repolarizing K + currents. Indeed, voltage-clamp recordings revealed that palmitate:BSA reversibly and selectively increased peak outward voltage-gated K + (Kv) current amplitudes by 20 ± 2%, whereas inwardly rectifying K + (Kir) currents and voltage-gated Ca 2+ currents were unaffected. Further analyses revealed that the individual Kv current components I to,f , I K,slow and I ss , were all increased (by 12 ± 2 %, 37 ± 4 % and 34 ± 4, respectively) in cells exposed to palmitate:BSA. Consistent with effects on both components of I K,slow (I K,slow1 and I K,slow2 ) the magnitude of the palmitate-induced increase was attenuated in ventricular myocytes isolated from animals in which the Kv1.5 (I K,slow1 ) or the Kv2.1 (I K,slow2 ) locus was disrupted and I K,slow1 or I K,slow2 is eliminated. Both the enhancement of I K,slow and the negative inotropic effect of palmitate:BSA were reduced in the presence of the Kv1.5 selective channel blocker, diphenyl phosphine oxide-1 (DPO-1). Taken together, these results suggest that elevations in circulating saturated free fatty acids, as occurs in diabetes, can directly augment repolarizing myocardial Kv currents and impair excitation-contraction coupling.

Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

“…Several studies have suggested that FAs or FA-mediated changes may influence myocardial calcium handling (17,47,24). The present study supports this view by showing that elevated FAs increase the oxygen cost for EC coupling.…”

“…The present study supports this view by showing that elevated FAs increase the oxygen cost for EC coupling. In cardiomyocytes, elevated palmitate has been reported to decrease Ca 2ϩ transients and fractional shortening (16,24). Whereas Fauconnier et al (16) reported that FA reduced SR Ca 2ϩ content and linked the changes in Ca 2ϩ handling and cell shortening, Haim et al (24) reported that these changes were not associated with altered SR Ca 2ϩ content but to increased peak outward voltage-gated K ϩ current amplitudes, leading to shortening of the action potential duration.…”

“…In cardiomyocytes, elevated palmitate has been reported to decrease Ca 2ϩ transients and fractional shortening (16,24). Whereas Fauconnier et al (16) reported that FA reduced SR Ca 2ϩ content and linked the changes in Ca 2ϩ handling and cell shortening, Haim et al (24) reported that these changes were not associated with altered SR Ca 2ϩ content but to increased peak outward voltage-gated K ϩ current amplitudes, leading to shortening of the action potential duration. Decreased Ca 2ϩ transient amplitude could predict a decrease in the oxygen cost for EC coupling, but as these experiments have been performed in isolated cardiomyocytes, it remains to be seen how an acute elevation of FA supply affects Ca 2ϩ homeostasis in the isolated heart.…”

“…In addition, there are reasons to believe that FAs or FAmediated changes may influence Ca 2ϩ handling. FAs have been shown to affect Ca 2ϩ handling in isolated cardiomyocytes (16,24), increased ROS production is known to affect ion transport mechanisms (21, 54), and there are studies suggesting a link between UCP and excitation-contraction (EC) coupling (52). We therefore hypothesized that the elevation of FA would alter the oxygen cost of EC coupling.…”

Dynamic cardiac PET imaging: Technological improvements advancing future cardiac health

“…34 The three main metabolic substrates of the heart are carbohydrates, fatty acids, and ketone bodies with exogenous fatty acids accounting for 60%-70% of the energy production in the normal heart. 35 In health, the myocardium increases fatty acid metabolism with an acute reduction in mechanical function, 36 but conversely acute reduction in myocardial fatty acid metabolism in cardiomyopathy is also associated with impaired function. 37 In the case of pressure overload, we found in studies using the SHR an increased reliance on carbohydrate oxidation in an attempt to maintain contractile function with a decline in fatty acid and oxygen utilization.…”