Increased expression of renal neutral endopeptidase in severe heart failure

Knecht, Mathias; Pagel, Ines; Langenickel, Thomas; Philipp, Sebastian; Scheuermann-Freestone, Michaela; Willnow, Thomas E.; Bruemmer, Dennis; Graf, Kristof; Dietz, Rainer; Willenbrock, Roland

doi:10.1016/s0024-3205(02)01990-2

Cited by 67 publications

(55 citation statements)

References 32 publications

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“…On the other hand, LVEDP 24 h after ascending aortic banding was reported as 1.35 times higher than the sham group (P Ͻ 0.05) (3). Moreover, Knecht et al (15) tested three different heart failure models of rats, namely, aortocaval shunt, aortic banding, and myocardial infarction. Thirty days after the operation, plasma atrial natriuretic peptide (ANP) levels were 314 Ϯ 66 (control), 998 Ϯ 207 (shunt), 921 Ϯ 96 (banding), and 1,675 Ϯ 239 pmol/l (infarction).…”

Section: Discussionmentioning

confidence: 99%

Activation of regenerating geneRegin rat and human hearts in response to acute stress

Kiji¹,

Dohi²,

Takasawa³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Recently, the regenerating gene ( Reg) has been documented to play an important role in various regenerating tissues, but it is unknown whether the Reg gene could be activated in the heart. The aim of this study was to reveal the transcriptional activation of Reg in the heart in response to heart stress. We first found REG-1 protein expression in human hearts obtained from autopsied patients who died of myocardial infarction. REG protein was immunohistochemically stained in a fine granular pattern in the cytoplasm of cardiomyocytes. To demonstrate the activation profiles of Reg gene expression in the heart, we quantified the levels of Reg-1 mRNA in rat hearts after coronary artery ligation using real-time RT-PCR. Transient Reg-1 mRNA activation, peaking at 12 h after coronary ligation, was observed mainly in the atria, which was sevenfold higher compared with hearts with pressure overload due to aortic constriction. In contrast, Reg receptor mRNA was expressed intensely in damaged ventricles. Furthermore, Western blot analysis showed the corresponding pattern of Reg protein secretion into the serum after loading, and circulating levels of the protein after myocardial infarction were higher than those after aortic constriction. In conclusion, our results demonstrate for the first time the presence of the Reg/Reg receptor system in damaged hearts. In view of emerging evidence of Reg for tissue regeneration in a variety of tissues/organs, it is proposed that the damaged heart may be a target for Reg action and that Reg may protect against acute heart stress.

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Section: Discussionmentioning

confidence: 99%

Activation of regenerating geneRegin rat and human hearts in response to acute stress

Kiji¹,

Dohi²,

Takasawa³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…The infrarenal Aortocaval Shunt (ACS) in male Wistar rats (weight on average 250 g) was used as a model of volume overload-induced heart failure as previously described [5][6][7]. Sham-operated rats used as controls were treated identically, except that no puncture of the vessels was performed.…”

Section: Methodsmentioning

confidence: 99%

“…We used the model of aortocaval shunt induced cardiac failure [5][6][7]. To identify the different properties of these substances we used the ACS model, in which fibrosis is negligible.…”

Section: Introductionmentioning

confidence: 99%

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Philipp¹

2012

J Clin Exp Cardiolog

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Introduction: Matrix reorganization and collagen formation have been suggested to be responsible for cardiac remodeling. Recently, Hypoxia Inducible Factors (HIF) has been shown to be also involved. To differentiate the pathogenesis of cardiac remodeling we used two different prolyl 4-hydroxylase (P4H) inhibitors, FG 0041 known for its potential in reducing collagen formation, FG 2216 for its capability to induce HIF. This study was performed to analyze whether the beneficial effects of P4-HI are mediated by induction of HIF or by effects on collagen metabolism.Methods: 8-week-old Wistar rats either had sham operations (n=14) or received Aortocaval Shunt (ACS). From day 2 rats received P4-HI (n=10 for each P4-HI) or vehicle (n=15) by oral gavage. Echocardiography was performed 28 days after ACS; hemodynamic measurements were done after 30 days. Activity of the metalloproteinase 2 and its inhibitor (TIMP), mRNA levels of CTGF, TGFß1, ITGß1 and Collagen I and III protein were measured.Results: After 30 days both HIF was induced in ACS. Treatment with FG 2216 led to an increase of HIF after 30 days compared to FG 0041 and vehicle. Only FG 2216 prevented left ventricular end-diastolic (7.9 mm vs. 9.8 mm; p<0.001) and end-systolic (4.1 vs. 6.0 mm, p<0.001) dilatation and improved left ventricular ejection fraction (85% vs. 74%, p<0.05). Heart weight (1416 ± 71 vs. 1871 ± 51 mg, p<0.001) and lung weight, as a marker for heart failure, (1958 ± 102 mg vs. 2276 ± 105 mg, p<0.05) were lower in the group receiving FG 2216. Collagen protein and metalloproteinase activity accompanying ACS were significantly decreased by FG 0041, but not by FG 2216. Conclusion:Induction of HIF improves cardiac function and reduces cardiac hypertrophy independent of changes in mRNA, collagen protein or metalloproteinase activity in this model of hypertrophy. Thus FG 2216 affects remodeling by directly targeting cardiomyocytes and has negligible effect on collagen production or extracellular matrix composition.

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“…NEP (EC 3.4.24.11), known also as neprilysin, enkephalinase, common acute lymphocytic leukaemia antigen (CALLA) or CD10, is a membranebound metallo-endopeptidase widely expressed in the vasculature (Turner, 2003). Increased NEP activity that could induce a biological resistance to NP action has been reported in heart failure patients (Knecht et al, 2002). In the present study, we investigated the putative presence and the functional role of PDE-5A and NEP in the regulation of cGMP signalling and in the lipolysis mediated by ANP in isolated human adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase‐5A and neutral endopeptidase activities in human adipocytes do not control atrial natriuretic peptide‐mediated lipolysis

Moro

Klimčáková

Lafontan

et al. 2007

British J Pharmacology

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Background and purpose: Atrial natriuretic peptide (ANP) stimulates lipolysis in human adipocyte through a cGMP signalling pathway, the regulation of which is poorly known. Since phosphodiesterases (PDE) and neutral endopeptidase (NEP) play a major role in the regulation of the biological effects of natriuretic peptides in the cardiovascular and renal systems, we investigated whether these mechanisms could regulate cGMP signalling and ANP-mediated lipolysis in human adipocytes. Experimental approach: The presence of cGMP-specific PDE and NEP in differentiated pre-adipocytes and in mature adipocytes was evaluated by real-time qPCR and Western blot. The effect of non-selective and selective inhibition of these enzymes on ANP-mediated cGMP signalling and lipolysis was determined in isolated mature adipocytes. Key results: PDE-5A was expressed in both pre-adipocytes and adipocytes. PDE-5A mRNA and protein levels decreased as preadipocytes differentiated (10 days). PDE-5A is rapidly activated in response to ANP stimulation and lowers intracellular cGMP levels. Its selective inhibition by sildenafil partly prevented the decline in cGMP levels. However, no changes in baseline-and ANP-mediated lipolysis were observed under PDE-5 blockade using various inhibitors. In addition, NEP mRNA and protein levels gradually increased during the time-course of pre-adipocyte differentiation. Thiorphan, a selective NEP inhibitor, completely abolished NEP activity in human adipocyte membranes but did not modify ANP-mediated lipolysis. Conclusions and implications: Functional PDE-5A and NEP activities were present in human adipocytes, however these enzymes did not play a major role in the regulation of ANP-mediated lipolysis.

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Increased expression of renal neutral endopeptidase in severe heart failure

Cited by 67 publications

References 32 publications

Activation of regenerating geneRegin rat and human hearts in response to acute stress

Activation of regenerating geneRegin rat and human hearts in response to acute stress

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Phosphodiesterase‐5A and neutral endopeptidase activities in human adipocytes do not control atrial natriuretic peptide‐mediated lipolysis

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