Hypercontractile Cardiac Phenotype in Mice with Migraine-Associated Mutation in the Na(+),K(+)-ATPase α(2)-Isoform

Two α-isoforms of the Na(+),K(+)-ATPase (α(1) and α(2)) 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 α(2)-isoform (G301R; α(2)(+/G301R) mice) have decreased expression of cardiac α(2)-isoform but elevated expression of the α(1)-isoform. We aimed to investigate the contribution of the α(2)-isoform function to the cardiac phenotype of α(2)(+/G301R) hearts. We hypothesized that α(2)(+/G301R) hearts exhibit greater contractility due to reduced expression of cardiac α(2)-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 α(2)(+/G301R) hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α(2)(+/G301R) hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α(2)(+/G301R) hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α(2)(+/G301R) hearts, which was associated with increased systolic work.