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Dilated cardiomyopathy alters the expression patterns of CAR and other adenoviral receptors in human heart

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Abstract

Gene therapy trials for heart failure have demonstrated the key role of efficient gene transfer in achieving therapeutic efficacy. An attractive approach to improve adenoviral gene transfer is to use alternative virus serotypes with modified tropism. We performed a detailed analysis of cardiac expression of receptors for several adenovirus serotypes with a focus on differential expression of CAR and CD46, as adenoviruses targeting these receptors have been used in various applications. Explanted hearts from patients with DCM and healthy donors were analyzed using Q-RT-PCR, western blot and immunohistochemistry. Q-RT-PCR and Western analyses revealed robust expression of all receptors except CD80 in normal hearts with lower expression levels in DCM. Immunohistochemical analyses demonstrated that CD46 expression was somewhat higher than CAR both in normal and DCM hearts with highest levels of expression in intramyocardial coronary vessels. Total CAR expression was upregulated in DCM. Triple staining on these vessels demonstrated that both CAR and CD46 were confined to the subendothelial layer in normal hearts. The situation was clearly different in DCM, where both CAR and CD46 were expressed by endothelial cells. The induction of expression of CAR and CD46 by endothelial cells in DCM suggests that viruses targeting these receptors could more easily gain entry to heart cells after intravascular administration. This finding thus has potential implications for the development of targeted gene therapy for heart failure.

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Acknowledgments

The authors have no conflicts of interest. We thank Sari Pitkänen for her advice and contribution to the histological stainings, Marjo Hakkarainen and Susanna Pyökäri (Turku Centre for Biotechnology) for their expertise on cell culture and viral vectors and Seija Lindqvist (University of Turku Central Animal Laboratory) for animal care. Mikko Simolin, Suvi Syväranta, the heart transplantation coordinators and the cardiac transplantation team of the Helsinki University Hospital are thanked for help in collection of the cardiac specimens. This work was supported by the Academy of Finland, Finnish Medical Foundation, Turku University Central Hospital, Turku University Foundation, Cancer Foundation of South-Western Finland, Turku Graduate School of Biomedical Sciences and the Finnish Foundation for Cardiovascular Research. Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.

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Authors and Affiliations

  1. Turku Centre for Biotechnology, Åbo Academy, University of Turku, Tykistökatu 6 B 5th Floor, 20520, Turku, Finland

    Raine Toivonen & Mikko Savontaus

  2. Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland

    Raine Toivonen & Mikko Savontaus

  3. Turku Graduate School of Biomedical Sciences, Åbo Academy, University of Turku, Turku, Finland

    Raine Toivonen

  4. Wihuri Research Institute, Helsinki, Finland

    Mikko I. Mäyränpää & Petri T. Kovanen

  5. Department of Medicine, University of Turku, Turku, Finland

    Mikko Savontaus

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  1. Raine Toivonen
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  2. Mikko I. Mäyränpää
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Correspondence to Mikko Savontaus.

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Toivonen, R., Mäyränpää, M.I., Kovanen, P.T. et al. Dilated cardiomyopathy alters the expression patterns of CAR and other adenoviral receptors in human heart. Histochem Cell Biol 133, 349–357 (2010). https://doi.org/10.1007/s00418-009-0666-1

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