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(Circulation Research. 2005;97:928.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure

Götz Münch, Kai Rosport, Andreas Bültmann, Christine Baumgartner, Zhongmin Li, Lien Laacke, Martin Ungerer

From the ProCorde GmbH, Martinsried, Germany.

Correspondence to Dr G. Münch or Prof Dr M. Ungerer, ProCorde, Fraunhoferstr. 9, D-82152 Martinsried, Germany. E-mail muench{at}procorde.com or ungerer@procorde.com

A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and ß-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameter: in GCP-overexpressing failing rabbits (GFP-CHF), 17.4±0.4 mm; in uptake-1–CHF rabbits, 15.6±0.6 mm) and systolic contractility (fractional shortening: GFP-CHF, 20.7±0.6%; uptake-1–CHF, 27.3±0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 µg/kg: GFP-CHF, 6964±230 mm Hg/sec; uptake-1–CHF, 7660±315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 µg/kg: GFP-CHF: –3960±260 mm Hg/sec; uptake-1–CHF, –4910±490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5±1.2 mm Hg; uptake-1–CHF, 5.6±0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure.

Key Words: heart failure • catecholamines • norepinephrine transporter • gene transfer • animal heart failure model

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