Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy

James R. Peña; Ariani C. Szkudlarek; Chad M. Warren; Lynley S. Heinrich; Robert D. Gaffin; Ganapathy Jagatheesan; Federica Del Monte; Roger J. Hajjar; Paul H. Goldspink; R. John Solaro; David F. Wieczorek; Beata M. Wolska

doi:10.1016/j.yjmcc.2010.09.010

Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy

James R. Peña, Ariani C. Szkudlarek, Chad M. Warren, Lynley S. Heinrich, Robert D. Gaffin, Ganapathy Jagatheesan, Federica Del Monte, Roger J. Hajjar, Paul H. Goldspink, R. John Solaro, David F. Wieczorek, Beata M. Wolska

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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 6weeks. 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 3months 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.

Original language	English
Pages (from-to)	993-1002
Number of pages	10
Journal	Journal of Molecular and Cellular Cardiology
Volume	49
Issue number	6
DOIs	https://doi.org/10.1016/j.yjmcc.2010.09.010
State	Published - Dec 2010

Keywords

Familial hypertrophic cardiomyopathy
Gene therapy
Serca2
Treatment

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10.1016/j.yjmcc.2010.09.010

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Peña, J. R., Szkudlarek, A. C., Warren, C. M., Heinrich, L. S., Gaffin, R. D., Jagatheesan, G., Del Monte, F., Hajjar, R. J., Goldspink, P. H., Solaro, R. J., Wieczorek, D. F., & Wolska, B. M. (2010). Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 49(6), 993-1002. https://doi.org/10.1016/j.yjmcc.2010.09.010

@article{8fa0e3a03fae4bca881a4af51b414e32,

title = "Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy",

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 6weeks. 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 3months 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.",

keywords = "Familial hypertrophic cardiomyopathy, Gene therapy, Serca2, Treatment",

author = "Pe{\~n}a, {James R.} and Szkudlarek, {Ariani C.} and Warren, {Chad M.} and Heinrich, {Lynley S.} and Gaffin, {Robert D.} and Ganapathy Jagatheesan and {Del Monte}, Federica and Hajjar, {Roger J.} and Goldspink, {Paul H.} and Solaro, {R. John} and Wieczorek, {David F.} and Wolska, {Beata M.}",

note = "Funding Information: These studies were supported by NIH RO1 HL79032 (BMW), HL64035 (RJS, BMW), T32 HL07692 (RDG), RO1HL22231 (RJS), PO1 HL62426 (RJS), RO1 HL81680 (DFW), R01 HL078691 (RJH), HL71763 (RJH), HL80498 (RJH), HL83156 (RJH) and a Leducq Transatlantic Network (RJH) grant. ",

year = "2010",

month = dec,

doi = "10.1016/j.yjmcc.2010.09.010",

language = "English",

volume = "49",

pages = "993--1002",

journal = "Journal of Molecular and Cellular Cardiology",

issn = "0022-2828",

publisher = "Academic Press",

number = "6",

}

Peña, JR, Szkudlarek, AC, Warren, CM, Heinrich, LS, Gaffin, RD, Jagatheesan, G, Del Monte, F, Hajjar, RJ, Goldspink, PH, Solaro, RJ, Wieczorek, DF & Wolska, BM 2010, 'Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy', Journal of Molecular and Cellular Cardiology, vol. 49, no. 6, pp. 993-1002. https://doi.org/10.1016/j.yjmcc.2010.09.010

TY - JOUR

T1 - Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy

AU - Peña, James R.

AU - Szkudlarek, Ariani C.

AU - Warren, Chad M.

AU - Heinrich, Lynley S.

AU - Gaffin, Robert D.

AU - Jagatheesan, Ganapathy

AU - Del Monte, Federica

AU - Hajjar, Roger J.

AU - Goldspink, Paul H.

AU - Solaro, R. John

AU - Wieczorek, David F.

AU - Wolska, Beata M.

N1 - Funding Information: These studies were supported by NIH RO1 HL79032 (BMW), HL64035 (RJS, BMW), T32 HL07692 (RDG), RO1HL22231 (RJS), PO1 HL62426 (RJS), RO1 HL81680 (DFW), R01 HL078691 (RJH), HL71763 (RJH), HL80498 (RJH), HL83156 (RJH) and a Leducq Transatlantic Network (RJH) grant.

PY - 2010/12

Y1 - 2010/12

N2 - 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 6weeks. 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 3months 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.

AB - 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 6weeks. 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 3months 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.

KW - Familial hypertrophic cardiomyopathy

KW - Gene therapy

KW - Serca2

KW - Treatment

UR - http://www.scopus.com/inward/record.url?scp=78149412295&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2010.09.010

DO - 10.1016/j.yjmcc.2010.09.010

M3 - Article

C2 - 20854827

AN - SCOPUS:78149412295

SN - 0022-2828

VL - 49

SP - 993

EP - 1002

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

IS - 6

ER -

Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy

Abstract

Keywords

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