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(Circulation. 2003;107:876.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Induction of Coxsackievirus-Adenovirus–Receptor Expression During Myocardial Tissue Formation and Remodeling

Identification of a Cell-to-Cell Contact–Dependent Regulatory Mechanism

Henry Fechner, DVM; Michel Noutsias, MD; Carsten Tschoepe, MD; Kerstin Hinze, DVM; Xiaomin Wang, BSc; Felicitas Escher, MD; Matthias Pauschinger, MD; Dick Dekkers, BSc; Roland Vetter, MD; Martin Paul, MD; Jos Lamers, PhD; Heinz-Peter Schultheiss, MD; Wolfgang Poller, MD

From the Department of Cardiology and Pneumology (H.F., M.N., C.T., K.H., X.W., F.E., M. Pauschinger, H.-P.S., W.P.), Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center (R.V., M. Paul), and Department of Virology, Faculty of Veterinary Medicine (K.H.), Freie Universität Berlin, Germany; and the Department of Biochemistry, Cardiovascular Research Institute COEUR, Erasmus University, Rotterdam, the Netherlands (D.D., J.L.).

Correspondence to Wolfgang Poller, MD, Benjamin Franklin Medical Center, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail 100270.2245{at}compuserve.com

Background— The coxsackievirus-adenovirus receptor (CAR) was cloned as a receptor for both viruses, but its primary biological functions and regulatory mechanisms are unknown. CAR was low in healthy adult myocardium, whereas strong CAR reexpression was observed in human dilated cardiomyopathy. The molecular mechanisms of CAR induction in cardiomyocytes are unknown.

Methods and Results— We report on CAR regulation during development, CAR induction after myocardial infarction, and cell-to-cell contact–dependent CAR regulation in the rat. The high CAR expression during development in various organs decreased up to 190-fold after birth. After infarction resulting in severe cardiac dysfunction (dP/dt_max, -53%; dP/dt_min, -58%; left ventricular pressure, -45%), CAR was induced locally in cardiomyocytes of the infarct zone, where it was also expressed by capillary-like CD31⁺ structures and CD18⁺ interstitial cells, whereas it remained confined to subendothelial layers of arterioles and venules. In cultured cardiomyocytes, endothelin-1, cardiotrophin-1, leukemia-inhibiting factor, and cyclic stretch had no effect on CAR, whereas at high versus low cell density, CAR was suppressed up to 10-fold (P=0.006). Conditioned media from low- or high-density cardiomyocytes or cardiofibroblasts had no effect.

Conclusions— The locally confined CAR upregulation after infarction makes induction by various humoral factors unlikely, because cardiac dysfunction results in high activities of sympathetic and renin-angiotensin systems and cytokines. The cell culture experiments identify a cell-to-cell contact–dependent mechanism of CAR regulation. Further characterization of the signals linking cell-to-cell interactions to CAR gene expression may provide insight into mechanisms and functional consequences of the generalized CAR induction in dilated cardiomyopathy, and of its local induction after myocardial infarction.

Key Words: viruses • receptors • signaling • myocardial infarction • remodeling

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