Abstract 24070: Cardiac-Specific Overexpression Of Caveolin-3 Expedites Cardiac Relaxation After Adrenergic Stimulation

Abstract

Introduction: Caveolae are membrane localized signaling platforms that compartmentalize signal transduction proteins such as GPCRs. Previous studies from our laboratory have demonstrated that overexpression of caveolin-3 in cardiac myocytes (Cav3 OE) protects against pressure-overload induced heart failure. Additionally, Cav3 OE mice present increased heart rate variability with lower nocturnal heart rates, but the mechanisms behind these phenotypes remain unclear. Hypothesis: Since Cav3 OE mice are protected from stressful cardiac stimuli, we tested the rationale that Cav3 OE hearts may show altered parasympathetic control of cardiac responses to adrenergic stimulation. Methods: Cav3 OE mice and transgene negative littermate controls (Ctrl) (12-16-week-old, n=10-11 each) were anesthetized with isoflurane and cardiac contractility was assessed by echocardiography at baseline. Isoprenaline (Isuprel USP [Iso], 300 nM i.p.) was administered ~10 min after baseline recordings and cardiac function recorded at 2 min, 5 min, and 10-15 min after Iso. The same animal cohort received a single atropine injection (2 mg/kg i.p) 20 min before isoflurane anesthesia and Iso challenge echocardiography was performed as described above. Results: At baseline, no differences in cardiac contractility (% ejection fraction, %EF±SD) were detected between the two groups ~68±8 %EF. After Iso injection cardiac contractility was increased to ~91±3 %EF in both genotypes at 2 min; however, in Cav3 OE mice cardiac contractility recovered to 83±3 %EF by 5 min post Iso challenge whereas Ctrl animals maintained increased contractility of 92±3 %EF (p < 0.001). Importantly, Cav3 OE mice pre-treated with atropine no longer showed increased recovery at 5 min or 10-15 post Iso (p = 0.007). A three-way ANOVA of the time-course after Iso injection found a significant effect of atropine on the responses of Cav3 OE versus Ctrl hearts to Iso (p = 0.007). Conclusion: We show for the first time that Cav3 OE mice show a faster recovery from hypercontractility after isoproterenol stimulation. Since atropine abrogated this recovery, these data suggest that Cav3 OE mice exhibit increased parasympathetic tone that may be responsible for improved stress adaptation and heart rate variability.