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Migraine-Associated Mutation in the Na,K-ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function. / Staehr, Christian; Rohde, Palle Duun; Krarup, Nikolaj Thure et al.
In: Journal of the American Heart Association, Vol. 11, No. 7, e021814, 04.2022.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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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 - Bøtker, Hans Erik
AU - Aalkjaer, Christian
AU - Matchkov, Vladimir
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - heart failure
KW - migraine
KW - mitochondrial function
KW - Na,K‐ATPase
KW - oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85128245309&partnerID=8YFLogxK
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 - e021814
ER -