title: Cardiac overexpression of the norepinephrine transporter uptake-1 results in marked improvement of heart failure.
abstract: 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 beta-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 microg/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 microg/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.
authors.affiliation: ProCorde GmbH, Martinsried, Germany. muench@procorde.com
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
authors.forename: Kai
authors.initials: K
authors.lastname: Rosport
authors.forename: Andreas
authors.initials: A
authors.lastname: Bültmann
authors.forename: Christine
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Li
authors.forename: Lien
authors.initials: L
authors.lastname: Laacke
authors.forename: Martin
authors.initials: M
authors.lastname: Ungerer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015316:Genetic Therapy; D006367:HeLa Cells; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D016716:PC12 Cells; D011817:Rabbits; D051381:Rats; D019076:Transgenes; D018487:Ventricular Dysfunction, Left / Q000628:therapy; D015430:Weight Gain
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D009638:Norepinephrine