TY - JOUR

T1 - Migraine-Associated Mutation in the Na,K-ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function

AU - Staehr, Christian

AU - Rohde, Palle Duun

AU - Krarup, Nikolaj Thure

AU - Ringgaard, Steffen

AU - Laustsen, Christoffer

AU - Johnsen, Jacob

AU - Nielsen, Rikke

AU - Beck, Hans Christian

AU - Morth, Jens Preben

AU - Lykke-Hartmann, Karin

AU - Jespersen, Nichlas Riise

AU - Abramochkin, Denis

AU - Nyegaard, Mette

AU - Botker, Hans Erik

AU - Aalkjaer, Christian

AU - Matchkov, Vladimir

PY - 2022

Y1 - 2022

N2 - 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 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.

AB - 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 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.

KW - heart failure

KW - migraine

KW - mitochondrial function

KW - Na

KW - K-ATPase

KW - oxidative stress

KW - NA+-K+-ATPASE

KW - OXIDATIVE STRESS

KW - CA2+ TRANSIENTS

KW - BLOOD-PRESSURE

KW - HEART

KW - PUMP

KW - ISOFORM

KW - INHIBITION

KW - ALPHA-2

KW - DYSFUNCTION

U2 - 10.1161/JAHA.121.021814

DO - 10.1161/JAHA.121.021814

M3 - Journal article

C2 - 35289188

VL - 11

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 7

M1 - 021814

ER -