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Development of cardiomyopathy in response to chronic β‐adrenegric stimulation of transgenic mouse overexpressing the exon‐22 isoform of the human Ca v 1.2 channel α1C subunit as revealed by magnetic resonance imaging
Author(s) -
Asemu Girma,
Fishbein Kenneth,
Canuto Holly,
Spencer Richard,
Soldatov Nikolai,
Abernethy Darrell
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a583-a
Subject(s) - medicine , gene isoform , cardiomyopathy , genetically modified mouse , endocrinology , ejection fraction , transgene , stimulation , exon , basal (medicine) , protein subunit , dilated cardiomyopathy , muscle hypertrophy , chemistry , cardiology , biology , heart failure , gene , biochemistry , insulin
Ca v 1.2 calcium channels are composed of the α 1C , β, and α 2 δ subunits and play a central role in controlling cardiac functions. Previously we found that alternative splicing of the pore‐forming α 1C subunit is affected by atherosclerosis. The molecular signature of the effect is an appearance of the exon‐22 isoform of the α 1C subunit that is absent from non‐diseased artery. Here, we generated transgenic mice (TG 22+ ) overexpressing the human α 1C22 splice variant. Magnetic resonance imaging (MRI) was used to investigate the cardiovascular phenotype in the basal state, as well as during chronic isoproterenol (IP) infusion (30 or 45 mg/kg/day, for 7 days). Chronic IP stress significantly increased left ventricular (LV) mass and LV to body weight ratio in both wild type (WT) and TG 22+ . MRI analysis also demonstrated that chronic IP stress increased the LV end‐systolic volume in both WT and TG 22+ vs. vehicle‐treated groups. Further, IP‐induced stress in TG 22+ mice significantly decreased LV ejection fraction and markedly increased the LV end‐systolic epicardial diameter as compared to the IP‐stressed WT mice. Thus, chronic IP stress in TG 22+ mice results in marked contractile dysfunction, greater than that seen in WT, that leads to LV hypertrophy and dilated cardiomyopathy. Supported by NIA intramural research program