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

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  • Rajkumar Rajanathan
  • Clàudia Vilaseca i. Riera
  • Tina Myhre Pedersen
  • Christian Staehr
  • Elena V. Bouzinova
  • Jens Randel Nyengaard
  • Thomsen, Morten Bækgaard
  • Hans Erik Bøtker
  • Vladimir V. Matchkov

Two α-isoforms of the Na+,K+-ATPase (α1 and α2) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the α2-isoform (G301R; α2+/G301R mice) have decreased expression of cardiac α2-isoform but elevated expression of the α1-isoform. We aimed to investigate the contribution of the α2-isoform function to the cardiac phenotype of α2+/G301R hearts. We hypothesized that α2+/G301R hearts exhibit greater contractility due to reduced expression of cardiac α2-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 µM). Atrial pacing was performed to investigate rate-dependent changes. The α2+/G301R hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α2+/G301R hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α2+/G301R hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α2+/G301R hearts, which was associated with increased systolic work.

Udgave nummer8
Antal sider21
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This research was funded by the Novo Nordisk Foundation, grant numbers NNF18OC0052021 and NNF19OC0056371.

Publisher Copyright:
© 2023 by the authors.

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