Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice

J. Patrick Gonzalez; Jayalakshmi Ramachandran; Eric Himelman; Myriam A. Badr; Chifei Kang; Julie Nouet; Nadezhda Fefelova; Lai Hua Xie; Natalia Shirokova; Jorge E. Contreras; Diego Fraidenraich

doi:10.1016/j.nmd.2018.01.012

Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice

J. Patrick Gonzalez, Jayalakshmi Ramachandran, Eric Himelman, Myriam A. Badr, Chifei Kang, Julie Nouet, Nadezhda Fefelova, Lai Hua Xie, Natalia Shirokova, Jorge E. Contreras, Diego Fraidenraich

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/−) mice were studied before (4–6 months) and after (10–15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/−) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/−) hearts. At time-point 4–6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/−) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/−) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/−) isolated hearts were also protected from arrhythmogenesis. At time-point 10–15 months, mdx:Cx43(+/−) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology.

Original language	English
Pages (from-to)	361-372
Number of pages	12
Journal	Neuromuscular Disorders
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.nmd.2018.01.012
State	Published - Apr 2018
Externally published	Yes

Keywords

Calcium handling
Cardiomyopathy
Connexin
Duchenne muscular dystrophy
Oxidative stress

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10.1016/j.nmd.2018.01.012

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Gonzalez, J. P., Ramachandran, J., Himelman, E., Badr, M. A., Kang, C., Nouet, J., Fefelova, N., Xie, L. H., Shirokova, N., Contreras, J. E., & Fraidenraich, D. (2018). Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice. Neuromuscular Disorders, 28(4), 361-372. https://doi.org/10.1016/j.nmd.2018.01.012

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title = "Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice",

abstract = "Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/−) mice were studied before (4–6 months) and after (10–15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/−) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/−) hearts. At time-point 4–6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/−) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/−) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/−) isolated hearts were also protected from arrhythmogenesis. At time-point 10–15 months, mdx:Cx43(+/−) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology.",

keywords = "Calcium handling, Cardiomyopathy, Connexin, Duchenne muscular dystrophy, Oxidative stress",

author = "Gonzalez, {J. Patrick} and Jayalakshmi Ramachandran and Eric Himelman and Badr, {Myriam A.} and Chifei Kang and Julie Nouet and Nadezhda Fefelova and Xie, {Lai Hua} and Natalia Shirokova and Contreras, {Jorge E.} and Diego Fraidenraich",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",

year = "2018",

month = apr,

doi = "10.1016/j.nmd.2018.01.012",

language = "English",

volume = "28",

pages = "361--372",

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AU - Gonzalez, J. Patrick

AU - Ramachandran, Jayalakshmi

AU - Himelman, Eric

AU - Badr, Myriam A.

AU - Kang, Chifei

AU - Nouet, Julie

AU - Fefelova, Nadezhda

AU - Xie, Lai Hua

AU - Shirokova, Natalia

AU - Contreras, Jorge E.

AU - Fraidenraich, Diego

PY - 2018/4

Y1 - 2018/4

N2 - Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/−) mice were studied before (4–6 months) and after (10–15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/−) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/−) hearts. At time-point 4–6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/−) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/−) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/−) isolated hearts were also protected from arrhythmogenesis. At time-point 10–15 months, mdx:Cx43(+/−) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology.

AB - Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/−) mice were studied before (4–6 months) and after (10–15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/−) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/−) hearts. At time-point 4–6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/−) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/−) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/−) isolated hearts were also protected from arrhythmogenesis. At time-point 10–15 months, mdx:Cx43(+/−) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology.

KW - Calcium handling

KW - Cardiomyopathy

KW - Connexin

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KW - Oxidative stress

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EP - 372

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

IS - 4

ER -

Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice

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