Staehr, Christian, Rohde, Palle Duun, Krarup, Nikolaj Thure, Ringgaard, Steffen, Laustsen, Christoffer, Johnsen, Jacob, Nielsen, Rikke, Beck, Hans Christian, Morth, Jens Preben, Lykke-Hartmann, Karin, Jespersen, Nichlas Riise, Abramochkin, Denis, Nyegaard, Mette, Botker, Hans Erik, Aalkjaer, Christian, Matchkov, Vladimir, Staehr, Christian, Rohde, Palle Duun, Krarup, Nikolaj Thure, Ringgaard, Steffen, Laustsen, Christoffer, Johnsen, Jacob, Nielsen, Rikke, Beck, Hans Christian, Morth, Jens Preben, Lykke-Hartmann, Karin, Jespersen, Nichlas Riise, Abramochkin, Denis, Nyegaard, Mette, Botker, Hans Erik, Aalkjaer, Christian, and Matchkov, Vladimir
Background Mutations in ATP1A2 gene encoding the Na,K-ATPase alpha(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 (alpha(+/G301R)(2) mice) and matching wild-type controls were compared. Reduced expression of the Na,K-ATPase alpha(2) isoform and increased expression of the alpha(1) isoform were observed in hearts from alpha(+/G301R)(2) mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8-month-old alpha(+/G301R)(2) mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old alpha(+/G301R)(2) 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 alpha(+/G301R)(2) 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 alpha(+/G301R)(2) mice. Conclusions Our findings suggest that ATP1A2 muta