Objectives: To develop an adult guinea pig model of lipotoxicity and explore the underlying mechanisms associated with changes in the expression of the delayed rectifier potassium current (I).
Background: Lipotoxicity may represent a common link among metabolic disorders and a higher vulnerability to arrhythmias.
Methods: Whole-cell patch clamp, and palmitic acid (PA, a potent inducer of lipotoxicity), were used to assess mechanisms of short-term (∼50 days) high-fat diet (HFD) feeding on atrial electrophysiology in guinea pig hearts and myocytes.
Results: HFD fed guinea pigs were significantly heavier, displayed hypertriglyceridemia and hypercholesterolemia; but no signs of hyperglycemia or inflammation compared to low-fat diet fed controls. Increasing cardiac PA levels, resulted in shortened atrial action potential duration, and increased I density. Inhibition of phosphoinositide 3-kinase (PI3K) prevented increases in I due to PA. Acute (≥1hr) exposure of atrial myocytes to exogenous PA (1 mM) increased the density of the rapid delayed rectifier potassium current I, while it was decreased with the unsaturated oleic acid (OA, 1 mM). Serine-threonine protein phosphatase-2 (PP2A) inhibition with cantharidin reversed the effect of OA on I.
Conclusion: Our data provide evidence of a novel lipotoxic guinea pig model with signs of vulnerability to arrhythmias. Inhibition of PA/PI3K/I and/or activation of the OA/PP2A/I pathways may be therapeutically beneficial for lipotoxic arrhythmias.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884136 | PMC |
| http://dx.doi.org/10.1016/j.bbrc.2019.09.051 | DOI Listing |
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