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: Götz Münch, Kai Rosport, Andreas Bültmann, Christine Baumgartner, Zhongmin Li, Lien Laacke, Martin Ungerer
• Journal: Circulation research (Circ Res) Vol. 97 Issue 9 Pg. 928-36 (Oct 28 2005) ISSN: 1524-4571 [Electronic] United States
• PMID: 16166553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Norepinephrine Plasma Membrane Transport Proteins
• SLC6A2 protein, human
• Norepinephrine

Topics

• Adenoviridae (genetics)
• Animals
• Genetic Therapy
• HeLa Cells
• Heart Failure (physiopathology, therapy)
• Humans
• Myocardial Contraction
• Myocardium (metabolism)
• Norepinephrine (metabolism)
• Norepinephrine Plasma Membrane Transport Proteins (genetics)
• PC12 Cells
• Rabbits
• Rats
• Transgenes
• Ventricular Dysfunction, Left (therapy)
• Weight Gain