Dilated cardiomyopathy alters the expression patterns of CAR and other adenoviral receptors in human heart.
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.
Toivonen
Raine
R
Turku Centre for Biotechnology, Abo Academy, University of Turku, Tykistökatu 6 B 5th Floor, 20520, Turku, Finland, raine.toivonen@btk.fi.
Mäyränpää
Mikko I
MI
Kovanen
Petri T
PT
Savontaus
Mikko
M
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C497857:CD46 protein, human; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus