Abstract 919: Neonatal Gene Transfer of SERCA2a Alters Hypertrophic Gene Expression and Improves the Response to β-Adrenergic Stimulation in a FHC α-Tropomyosin (Glu180Gly) Mouse Model
Familial hypertrophy cardiomyopathy (FHC) has been linked to numerous mutations in the contractile proteins and is known as a disease of the sarcomere. We have previously shown that transgenic (TG) mice expressing mutated α-tropomyosin (α-TM(Glu180Gly)) develop severe cardiac hypertrophy and diastolic dysfunction that is associated with increased myofilament sensitivity to Ca2+. We hypothesize that improving Ca2+ regulation in early neonatal life may delay or prevent the development of hypertrophy and cardiac dysfunction in TG mice. Therefore, adenoviral-SERCA2a was injected directly into the left ventricle of one day old non-transgenic (NTG) and TG mice. Likewise, Ad.LacZ was injected as a control. Expression of exogenous SERCA2a was detected up to 6 weeks in NTG and TG hearts injected with Ad.SERCAC2a by quantitative RT-PCR. Compared to TG-Ad.Lac hearts, the TG-Ad.SERCA2a hearts showed improved whole heart morphology. Moreover, there was also a significant decline in ANF and β-MHC expression detected by quantitative RT-PCR. Developed force (DF) in isolated papillary muscle from 2–3 week old TG-Ad.SERCA2a hearts was higher in the absence of isoproterenol (ISO) (DF, TG-Ad.SERCA2a 8.6 ± 1.5 mN/mm2 vs. TG 4.8 ± 0.5 mN/mm2), and in response to 1 μM of ISO (DF, TG-Ad.SERCA2a 14.8 ±1.2 mN/mm2 vs. TG 8.6 ± 1.5 mN/mm2) compared to non-infected TG hearts. In situ hemodynamic measurements showed that by 3 months the TG-Ad.SERCA2a hearts also had a significantly improved response to ISO compared to TG hearts not infected or TG-Ad.LacZ hearts. Our data strongly suggest that SERCA2a may be a useful therapeutic target in FHC models in which the primary defect results in diastolic dysfunction.