The Neuronal Norepinephrine Transporter in Experimental Heart Failure: Evidence for a Posttranscriptional Downregulation

Backs, Johannes; Haunstetter, Armin; Gerber, Stefan; Metz, J.; Borst, Mathias M.; Strasser, Ruth H.; Kübler, W.; Haass, Markus

doi:10.1006/jmcc.2000.1319

Cited by 102 publications

(98 citation statements)

References 46 publications

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“…To test whether sympathetic nerve function is preserved in SN-KO after TAC, sympathetic indices including NE tissue levels and metaiodobenzylguanidine (MIBG) uptake were determined. Depleted myocardial NE stores indicated a substantial increase in NE net secretion as an estimate for overactivation of the local cardiac sympathetic nervous system (24,25). Accordingly, we found left ventricular NE tissue levels to be decreased after TAC in Ctrl.…”

Section: Resultsmentioning

confidence: 53%

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Lehmann

Rostosky

Buss

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance In failing hearts, norepinephrine (NE) net release and endothelin-1 (ET1) levels are increased. ET1 receptor antagonists were successfully used in preclinical heart failure (HF) studies, but clinical studies did not show beneficial effects in HF patients. We found that mice lacking endothelin receptor A (ET A ) only in sympathetic neurons but not in cardiomyocytes were protected from the development of HF. Mechanistically, the presynaptic reuptake of NE within the heart was preserved in mice lacking ET A only in sympathetic neurons. These data provide an explanation of why patients in clinical studies do not benefit from ET1 receptor antagonists, because these patients are usually treated with β blockers, which interfere with the mechanism of action identified here.

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Section: Resultsmentioning

confidence: 53%

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Lehmann

Rostosky

Buss

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The latter phenomenon is due to its preserved neuronal re-uptake, via maintained function of the neuronal norepinephrine transporter. Together, these events concur to maintain proper left ventricular (LV) morphology and function, even under conditions of chronic cardiac stress due to pressure overload (3,4,39). As a major source of reactive oxygen species (ROS), MAO-A contributes to in vitro myocyte hypertrophy (6), ischemia/reperfusion (I/R) injury both in ex vivo (10) and in vivo models (5,31), heart failure and LV remodeling (25,42).…”

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confidence: 99%

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Kaludercic

Carpi

Nagayama

et al. 2014

Antioxidants & Redox Signaling

146

139

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Aims: Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. Results: In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B -/ -) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Innovation: Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Conclusion: Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria. Antioxid. Redox Signal. 20, 267-280.

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“…1 It has been demonstrated that an impaired neuronal norepinephrine (NE) reuptake via the NE transporter (NET) contributes to an enhanced NE net release. [2][3][4][5] As a consequence, depletion of cardiac NE stores and chronic overstimulation of adrenergic receptors leads to worsening of heart failure and sudden death, as well as to profound alterations of postreceptor signal coupling and cardiac remodeling. 6,7 Whereas some studies reported that an impaired NE reuptake was the result of a reduced NET density on cardiac sympathetic nerve endings, 5 other studies demonstrated a loss of sympathetic nerve endings, which occurred mainly in advanced stages of experimental CHF.…”

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confidence: 99%

“…14,15 To test the hypothesis of whether NGF improves the cardiac sympathetic nerve function in experimental CHF, NGF was directly injected into stellate ganglia of rats with transverse aortic constriction (TAC), which have been characterized previously by overt heart failure, depleted NE stores, and an impaired NE reuptake. 5,16 …”

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confidence: 99%

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

et al. 2006

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Abstract-An impairment of cardiac norepinephrine reuptake through the neuronal norepinephrine transporter promotes depletion of cardiac norepinephrine stores and local cardiac sympathetic activation in heart failure. Nerve growth factor regulates differentiation and survival of adult sympathetic cells and is decreased in failing hearts. We hypothesized that injection of nerve growth factor into stellate ganglia normalizes cardiac norepinephrine homeostasis in experimental heart failure. Rats with transverse aortic constriction characterized by heart failure, depleted cardiac norepinephrine stores, and impaired cardiac norepinephrine reuptake were used as an experimental model. Nerve growth factor (20 g) or saline was directly injected into left stellate ganglia 4 weeks after transverse aortic constriction. Thirty-two hours after injection, determinants of cardiac norepinephrine homeostasis were measured. As compared with saline, nerve growth factor refilled depleted cardiac norepinephrine stores and improved cardiac [ 3 H]-norepinephrine uptake into isolated perfused hearts of transverse aortic constricted rats. In addition, pharmacological blockade of the norepinephrine transporter led to a higher increase in the overflow of endogenous norepinephrine from hearts of nerve growth factor-injected than saline-injected transverse aortic constricted rats. Norepinephrine transporter mRNA levels and the density of cardiac sympathetic nerves were not changed. Thirty-two hours after nerve growth factor injection, echocardiography revealed an increase in fractional shortening as compared with 2 days before injection. In conclusion, nerve growth factor attenuates local cardiac sympathetic overdrive of hypertrophic hearts by improving cardiac norepinephrine reuptake and might represent a novel therapeutic principle in the treatment of heart failure.

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The Neuronal Norepinephrine Transporter in Experimental Heart Failure: Evidence for a Posttranscriptional Downregulation

Cited by 102 publications

References 46 publications

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

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