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

Abstract

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 ␤-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), 17.4Ϯ0.4 mm; in uptake-1-CHF rabbits, 15.6Ϯ0.6 mm) and systolic contractility (fractional shortening: GFP-CHF, 20.7Ϯ0.6%; uptake-1-CHF, 27.3Ϯ0.7%), 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 g/kg: GFP-CHF, 6964Ϯ230 mm Hg/sec; uptake-1-CHF, 7660Ϯ315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 g/kg: GFP-CHF: Ϫ3960Ϯ260 mm Hg/sec; uptake-1-CHF, Ϫ4910Ϯ490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5Ϯ1.2 mm Hg; uptake-1-CHF, 5.6Ϯ0.7 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 Ⅲ catecholamines Ⅲ norepinephrine transporter Ⅲ gene transfer Ⅲ animal heart failure model H eart failure is characterized by a marked increase in sympathoadrenergic activity. Increased systemic levels of norepinephrine (NE), which correlate to the prognosis of the patients, 1 and increased local cardiac spillover of catecholamines are 2 key elements observed in patients with heart failure. Cardiac NE spillover is the net result of NE release from nerve terminals and clearance of synaptic NE mainly caused by reuptake via the uptake carriers. A reduction of cardiac uptake-1 density or function has been documented in tissue samples of both human patients and animal models of the disease and might contribute to this increase in NE spillover. [2][3][4] A decrease of myocardial NE uptake-1 has also been found to correlate with age in humans. 5 Clinical studies of patients with terminal heart failure have shown an increased cardiac NE turnover at rest, 6,7 as well as a failure to reach...

Evaluation of LMI1195, a Novel 18 F-Labeled Cardiac Neuronal PET Imaging Agent, in Cells and Animal Models

“…1,2,25,26 In contrast, increased NET function by overexpressing NET in the heart, using adenoviral gene transfer, improved cardiac function in animals with HF. 27 Therefore, measuring cardiac NET function may be useful for monitoring the disease progression and cardiac events in patients with HF.…”

Designing Heart Performance by Gene Transfer

“…Accumulation of NE during hyperstimulation of ␤-AR was postulated to be a major cause of structural and functional impairment during heart failure (726). Efforts to improve local NE clearance using gene transfer of uptake-1 into rabbit hearts prior to pacing-induced heart failure acutely improved NE uptake, ␤ 1 -AR receptor, and SERCA2 expression, as well as diastolic and systolic contractile function, over a 2-wk time period (612). Gene transfer of uptake-1 had no significant influence on contractile function in nonfailing hearts.…”

Gene Therapy in Cardiovascular Disease

“…This protein is down-regulated during HF, which leads to an increase of extracellular catecholamine levels, resulting in a hyper-adrenergic state that it has a central role in the desensitization of the receptors. In rabbits with HF with an over-expression of the NE-uptake-1, the concentration of norepinephrine was kept near normal levels, and was associated with an improvement in cardiac function, and the cardiac hypertrophy was reverted, recovering the normal phenotype of the heart (Munch et al, 2005).…”

“…It is for this reason that new therapeutic approaches are required, focused to correct the molecular defects of HF. Among the molecular defects observed during HF, that have been explored as therapeutic targets, are the alterations in Ca 2+ handling during the excitation-contraction coupling (Hoshijima et al, 2002;Iwanaga et al, 2004;Kaprielian et al, 2002;Michele et al, 2004;Miyamoto et al, 2000;Most et al, 2004b;Most et al, 2007;Pleger et al, 2007;Pleger et al, 96 2005;Szatkowski et al, 2001), alterations in the -adrenergic receptors and their interaction with G proteins (Jones et al, 2004a;Koch, 2004;Maurice et al, 1999;Munch et al, 2005;Tevaearai et al, 2002), alterations of cellular signaling, including the members of the protein kinase C (PKC) family (Hambleton, 2006), and to the production of second messengers by the enzyme adenylyl cyclase (Lai et al, 2004). The apoptosis of cardiac myocytes also has been mentioned (Chatterjee et al, 2002;Tenhunen et al, 2006).…”