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Electrophysiological abnormalities in mice with genetic ablation of Rap1a GTPase
Author(s) -
Jeyaraj Selvi C,
Joshi Mandar S,
Huang Hong,
Unger Nicholas T,
ElDahdah N. Paul,
Wold Loren E,
Strauch Arthur R,
Elton Terry S,
Quilliam Lawrence A,
Bauer John A,
Chotani Maqsood A
Publication year - 2010
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.24.1_supplement.867.3
Subject(s) - medicine , qt interval , cardiology , endocrinology , potassium channel , in vivo , heart rate , rap1 , qrs complex , chemistry , blood pressure , biology , signal transduction , genetics
Rap1a, a member of the Ras‐like GTPase family, acts as a molecular switch coupling extracellular stimulation to intracellular signaling through cyclic AMP. The impact of Rap1 deficiency in heart function has yet to be defined. We tested the hypothesis that Rap1a null mice (Rap1A−/−) have abnormal ventricular excitation or contraction, using in vivo cardiovascular status measures by echocardiography, and ECGs (n=5/group) in comparison to wild‐type (WT) controls. At rest, no significant difference in heart rate, LV fractional shortening, or cardiac output, but slight reduction in systolic blood pressure were observed in the two groups. In contrast, significant increases in QT interval (41.4±4.1ms for WT and 57.6±2.5ms for Rap1A −/−; p<0.05), QRS duration (11.9±1.0ms for WT and 15.9±1.4ms for Rap1A −/−; p<0.05), and R‐R variability were observed in Rap1A−/− mice. Evaluation of the ERG1, long QT associated voltage‐activated potassium channel, with qRT‐PCR and Western blotting indicate a 2‐fold decrease in the mRNA and protein levels. Together, loss of Rap1A shows an impact on repolarizing mechanisms. Although the two Rap1 subtypes A and B are closely related, they are not functionally redundant, with Rap1A contributing to normal cardiac function. These findings suggest a novel genetic basis of prolonged QT interval and arrhythmia risks in vivo.