Coxsackie‐and‐adenovirus receptor mRNA expression in human heart failure

Sasse, Alexander; Wallich, Martina; Ding, Zhaoping; Goedecke, Axel; Schrader, Jürgen

doi:10.1002/jgm.411

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…Previously published data have demonstrated CAR receptor expression to be upregulated in DCM 12 to 34-fold in comparison with normal cardiac tissue, although expression levels were highly variable between samples (Noutsias et al 2001;Sasse et al 2003). We saw small differences in CAR expression levels between normal and DCM hearts with minor in-group variation.…”

Section: Discussionmentioning

confidence: 43%

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

Toivonen

Mäyränpää

Kovanen

et al. 2009

Histochem Cell Biol

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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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Section: Discussionmentioning

confidence: 43%

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

Toivonen

Mäyränpää

Kovanen

et al. 2009

Histochem Cell Biol

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“…This may be attributable to the difference of endogenous CAR expression between the two tissues. Considering that induction of CAR accompanies myocarditis [28] and its dramatic upregulation has recently been demonstrated in patients suffering from multiple diseases of the heart [29] including dilated cardiomyopathy, a pathological phenotype linked to persistent acute myocarditis, upregulation of the receptor may render the heart even more susceptible to further viral infection. Conversely, the low level of endogenous CAR expression in skeletal muscle may safeguard against the wide-spread viral infection seen in myocarditis and may be responsible for the less severe clinical features of myositis.…”

Section: Resultsmentioning

confidence: 99%

Isoform-specific expression of the Coxsackie and adenovirus receptor (CAR) in neuromuscular junction and cardiac intercalated discs

et al. 2004

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Background: The Coxsackie and adenovirus receptor (CAR) has a restricted expression pattern in the adult. In skeletal muscle, although CAR is expressed in immature fibers, its transcript levels are barely detectable in mature muscle. This is in contrast to the robust expression observed in the heart. However, both heart and skeletal muscle are susceptible to infection with the Coxsackie B virus which utilizes primarily CAR for cellular internalization. The specific point of viral entry in skeletal and heart muscle remains unknown.

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“…CAR expression within the myocardium is highest during embryonic life and appears to be downregulated after birth. However, expression within the heart is increased in disease states, including certain forms of cardiomyopathy, 7,39 and after myocardial infarction. 40 It is possible that the function of CAR during myocardial development is recapitulated in cardiac diseases and that CAR may act to inhibit cardiomyocyte proliferation after myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-Specific Deletion of the Coxsackievirus and Adenovirus Receptor Results in Hyperplasia of the Embryonic Left Ventricle and Abnormalities of Sinuatrial Valves

Chen

Zhou

et al. 2006

Circulation Research

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Abstract-The coxsackievirus and adenovirus receptor (CAR), which mediates infection by the viruses most commonly associated with myocarditis, is a transmembrane component of specialized intercellular junctions, including the myocardial intercalated disc; it is known to mediate cell-cell recognition, but its natural function is poorly understood. We used conditional gene targeting to investigate the possible functions of CAR during embryonic development, generating mice with both germline and tissue-specific defects in CAR expression. Homozygous germline deletion of CAR exon 2 or cardiomyocyte-specific gene deletion at embryonic day 10 (E10) mediated by Cre recombinase expressed under the control of the cardiac troponin T promoter resulted in death by E12.5; embryos showed marked cardiac abnormalities by E10.5, with hyperplasia of the left ventricular myocardium, distention of the cardinal veins, and abnormalities of sinuatrial valves. Within the hyperplastic left ventricle, increased numbers of proliferating cells were evident; persistent expression of N-myc in the hyperplastic myocardium and attenuated expression of the trabecular markers atrial natriuretic factor and bone morphogenic protein 10 indicated that proliferating cardiomyocytes had failed to differentiate and form normal trabeculae. In electron micrographs, individual CAR-deficient cardiomyocytes within the left ventricle appeared normal, but intercellular junctions were ill-formed or absent, consistent with the known function of CAR as a junctional molecule; myofibrils were also poorly organized. When cardiomyocyte-specific deletion occurred somewhat later (by E11, mediated by Cre under control of the ␣-myosin heavy chain promoter), animals survived to adulthood and did not have evident cardiac abnormalities. These results indicate that during a specific temporal window, CAR expression on cardiomyocytes is essential for normal cardiac development. In addition, the results suggest that CAR-mediated intercellular contacts may regulate proliferation and differentiation of cardiomyocytes within the embryonic left ventricular wall. Key Words: adhesion molecules Ⅲ cardiac development Ⅲ cardiomyopathy Ⅲ coxsackievirus receptor Ⅲ hyperplasia Ⅲ intercellular junctions Ⅲ mouse heart development T he coxsackievirus and adenovirus receptor (CAR) is a 46-kDa cell surface protein that mediates attachment and infection by group B coxsackieviruses and many adenoviruses. 1,2 CAR has been conserved during vertebrate evolution, with homologs identified in mammals, birds, frogs, and fish, 3 but its natural functions are not well understood. Recent work demonstrates that CAR mediates homotypic 4,5 and heterotypic 6 intercellular interactions and that it is a component of specialized intercellular junctions, including the epithelial tight junction 4 and the cardiac intercalated disc. 7 Although distinct CAR-mediated signals have not been defined, CAR expression in tumor cell lines leads to changes in the activity of cell cycle regulators that are associated with slower g...

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Coxsackie‐and‐adenovirus receptor mRNA expression in human heart failure

Cited by 20 publications

References 22 publications

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

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

Isoform-specific expression of the Coxsackie and adenovirus receptor (CAR) in neuromuscular junction and cardiac intercalated discs

Cardiomyocyte-Specific Deletion of the Coxsackievirus and Adenovirus Receptor Results in Hyperplasia of the Embryonic Left Ventricle and Abnormalities of Sinuatrial Valves

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