Migraine‐Associated Mutation in the Na,K‐ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function

Abstract

Background Mutations in ATP1A2 gene encoding the Na,K‐ATPase α 2 isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K‐ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2–associated G301R mutation in the Atp1a2 gene (α 2 +/G301R mice) and matching wild‐type controls were compared. Reduced expression of the Na,K‐ATPase α 2 isoform and increased expression of the α 1 isoform were observed in hearts from α 2 +/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8‐month‐old α 2 +/G301R mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3‐month‐old α 2 +/G301R mice were similar to wild‐type mice. Amplified Na,K‐ATPase–dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen‐activated protein kinase) signaling was observed in hearts from 8‐month‐old α 2 +/G301R mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure–associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´‐tetrachloro‐1,1´,3,3´‐tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8‐month‐old α 2 +/G301R mice. Conclusions Our findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K‐ATPase–dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.

Hypercontractile Cardiac Phenotype in Mice with Migraine-Associated Mutation in the Na+,K+-ATPase α2-Isoform

“…Previous evidence indicates that the cardiometabolic profile was changed in genetically modified mouse models under conditions of chronic elevation of intracellular Na + concentration ([Na + ] in ), which was associated with altered mitochondrial Ca 2+ handling [59]. In addition, this metabolic change involved the switch from fatty acid oxidation to glycolysis as the primary means of energy utilization, which was also reported for aged α 2 +/G301R mice, perhaps suggesting a similar mechanism at play [26]. In contrast, in the previous report, acute elevation of [Na + ] in by ouabain (75 µM) did not change the cardiometabolic profile, supporting the notion of distinct mechanisms of chronic and acute elevations of [Na + ] in [59].…”

“…We suggest that the heart rate may accommodate and offset the overall energy cost of the greater contractility in a compensatory manner in α 2 +/G301R hearts, compared with WT hearts. We previously reported a lower ejection fraction in aged α 2 +/G301R mice in vivo than in matching WT mice [26]. However, in an in vivo setting, vascular, humoral, and neuronal factors must also be considered in conjunction with cardiac function [54,55].…”

“…A previous investigation suggested a changed cardiac phenotype in aged mice but not in young α 2 +/G301R mice, and no difference between female and male mice of the same genotype was reported [ 26 ]. Due to their bigger body sizes, aged α 2 +/G301R male mice were previously studied in vivo [ 27 ].…”

“…It has been shown that the FHM2-associated mutation, G301R, leads to both impediment of protein translocation to the cell membrane and functional disarray of expressed mutated protein [ 24 , 25 ]. We have demonstrated that mice heterozygous for the FHM2-associated mutation (G301R; α 2 +/G301R ) are characterized by decreased expression of the α 2 -isoform but increased expression of the α 1 -isoform in their hearts [ 26 ]. This inverse expression of the α 1 - and the α 2 -isoforms in the α 2 +/G301R mouse model offers a unique opportunity for studying the isoform-specific Na + ,K + -ATPase contribution to cardiac contractility in a disease model relevant to human health.…”

“…This study demonstrates the significant role of the α 2 -isoform in the regulation of cardiac contractility in a murine model relevant to human disease, i.e., FHM2. We suggest that the chronic augmented cardiac contractility of α 2 +/G301R hearts may be implicated in the development of cardiometabolic abnormalities described in aged α 2 +/G301R mice [ 26 ].…”