Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy |
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| Institution: | 1. Department of Internal Medicine and Paediatrics, Faculty of Health Sciences, University of Buea, Buea, Cameroon;2. Health and Human Development (2HD) Research Network, Douala, Cameroon;3. Department of Internal Medicine, Douala General Hospital, Douala, Cameroon;4. Biochemistry Unit, Douala General Hospital Laboratory, Douala, Cameroon;5. Department of Biomedical Sciences, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon;6. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;7. National Obesity Centre, Yaounde Central Hospital, Yaounde, Cameroon;8. Department of Internal Medicine and Subspecialties, Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon;9. South African Medical Research Council, University of Cape Town, Cape Town, South Africa;1. Dipartimento di Fisica, Università di Roma Tor Vergata and INFN, Via della Ricerca Scientifica 1, 00133 Rome, Italy;2. College of Engineering and Computer Science (CECS), Australian National University, Canberra, ACT 0200, Australia;3. Dipartimento di Biochimica, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Rome, Italy;4. Istituto di Struttura della Materia, CNR, via del Fosso del Cavaliere 100, 00133 Rome, Italy;5. Centro Fermi - Museo Storico della Fisica e Centro Studi e Ricerche “Enrico Fermi”, Rome, Italy;1. School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252059, China;2. Institute of BioPharmceutical Research, Liaocheng University, Liaocheng 252059, China |
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| Abstract: | Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca2+ regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca2+ and diastolic dysfunction. A transgenic (TG) mouse model of FHC with a mutation in tropomyosin at position 180 was employed. Adenoviral-Serca2a (Ad.Ser) was injected into the left ventricle of 1-day-old non-transgenic (NTG) and TG mice. Ad.LacZ was injected as a control. Serca2a protein expression was significantly increased in NTG and TG hearts injected with Ad.Ser for up to 6 weeks. Compared to TG-Ad.LacZ hearts, the TG-Ad.Ser hearts showed improved whole heart morphology. Moreover, there was a significant decline in ANF and β-MHC expression. Developed force in isolated papillary muscle from 2- to 3-week-old TG-Ad.Ser hearts was higher and the response to isoproterenol (ISO) improved compared to TG-Ad.LacZ muscles. In situ hemodynamic measurements showed that by 3 months the TG-Ad.Ser hearts also had a significantly improved response to ISO compared to TG-Ad.LacZ hearts. The present study strongly suggests that Serca2a expression should be considered as a potential target for gene therapy in FHC. Moreover, our data imply that development of FHC can be successfully delayed if therapies are started shortly after birth. |
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