Protein kinases mediate anti-inflammatory effects of cannabidiol and
estradiol against high glucose in cardiac sodium channels
Abstract
Background and purpose. Cardiovascular anomalies are predisposing
factors for diabetes-induced morbidity and mortality. Recently, we
showed that high glucose induces changes in the biophysical properties
of Nav1.5 that could be strongly correlated to diabetes-induced
arrhythmia. However, the mechanisms underlying hyperglycemia-induced
inflammation, and how inflammation provokes cardiac arrhythmia, are not
well understood. We hypothesized that inflammation could mediate the
high glucose-induced biophyscial changes on Nav1.5 through protein
phosphorylation by protein kinases A and C. We also hypothesized that
this signaling pathway is, at least partly, involved in the
cardiprotective effects of CBD and E2. Experimental approach. To test
these ideas, we used Chinese hamster ovarian (CHO) cells transiently
co-transfected with cDNA encoding human Nav1.5 α-subunit under control,
a cocktail of inflammatory mediators or 100 mM glucose conditions (for
24 hours). We used electrophysiological experiments and action potential
modelling. Key Results. Inflammatory mediators, similar to 100 mM
glucose, right shifted the voltage dependence of conductance and steady
state fast inactivation and increased persistent current leading to
computational prolongation of action potential (hyperexcitability) which
could result in long QT3 arrhythmia. In addition, activators of PK-A or
PK-C replicated the inflammation-induced gating changes of Nav1.5.
Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially
deleterious effects provoked by high glucose/inflammation. Conclusions
and implications. These findings suggest that PK-A and PK-C may mediate
the anti-inflammatory effects of CBD and E2 against high glucose-induced
arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic
approach in diabetic postmenopausal population.