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

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 β-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 diameterin 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 shorteningGFP-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/kgGFP-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/kgGFP-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.