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| Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta(2)-adrenergic receptor gene delivery |
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| Author(s): Maurice JP, Hata JA, Shah AS, White DC, McDonald PH, Dolber PC, Wilson KH, Lefkowitz RJ, Glower DD, Koch WJ |
| Source: JOURNAL OF CLINICAL INVESTIGATION Volume: 104 Issue: 1 Pages: 21-29 Published: JUL 1999 |
| Times Cited: 114 References: 29 |
| Abstract: Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human beta(2)-AR (Adeno-beta(2)AR), to the :myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-beta(2)AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles of Adeno-beta(2)AR reproducibly produced 5- to 10-fold beta-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dt(max) as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of beta-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy. |
| Document Type: Article |
| Language: English |
| Reprint Address: Koch, WJ (reprint author), Duke Univ, Med Ctr, Dept Surg, Room 472,Med Sci Res Bldg,Box 2606,Res Dr, Durham, NC 27710 USA |
Addresses:
1. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
2. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
3. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
4. Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA |
| Publisher: AMER SOC CLINICAL INVESTIGATION INC, ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA |
| Subject Category: Medicine, Research & Experimental |
| IDS Number: 251WA |
| ISSN: 0021-9738 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |