Regulation of cardiac adrenomedullin-mRNA in different stages of experimental heart failure

Willenbrock, Roland; Langenickel, Thomas; Knecht, Mathias; Pagel, Ines; Höhnel, Klaus; Philipp, Sebastian; Dietz, Rainer

doi:10.1016/s0024-3205(99)00489-0

Cited by 15 publications

(10 citation statements)

References 22 publications

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“…Perhaps differences in the experimental models and the time frames utilized might explain these discrepancies. In regard to temporal profiles, Willenbrock and colleagues reported, contrary to some earlier findings, that ventricular adrenomedullin-RNA expression and adrenomedullin concentrations were up-regulated only in advanced stages of heart failure in rats with aortocaval shunts (26).…”

Section: Cardiac Renal and Vascular Adrenomedullin In Heart Failurementioning

confidence: 72%

Adrenomedullin in Heart Failure

et al. 2003

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Patients with heart failure have frequently been reported to show elevated levels of plasma adrenomedullin. These levels generally correlate with severity of hemodynamic dysfunction and also with neurohormonal indices which are activated according to the severity of heart failure. Furthermore, adrenomedullin gene expression in the heart and kidney is increased in experimental and clinical heart failure. A small number of studies have examined the responses to infusion of adrenomedullin in experimental and clinical heart failure. These studies have generally shown that infusion of adrenomedullin has beneficial hemodynamic effects and promotes maintenance or improvement in renal function, although most of these trials were of short duration. The available data suggest that adrenomedullin in the heart, kidney and plasma is increased

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Section: Cardiac Renal and Vascular Adrenomedullin In Heart Failurementioning

confidence: 72%

Adrenomedullin in Heart Failure

et al. 2003

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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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“…Increased plasma levels of AM have been detected in hypertension (Sumimoto et al, 1997), myocardial infarction (Nagaya et al, 2000), and heart failure (Willenbrock et al, 1999); levels are greater in hypertensive patients with LVH than those without underlying LVH (Sumimoto et al, 1997). Cardiomyocytes express the precursor peptide and secrete mature AM .…”

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confidence: 99%

Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension

Zhao

Bell

Smith

et al. 2005

J Pharmacol Exp Ther

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Adrenomedullin (AM) and intermedin (IMD; adrenomedulln-2) are vasodilator peptides related to calcitonin gene-related peptide (CGRP). The actions of these peptides are mediated by the calcitonin receptor-like receptor (CLR) in association with one of three receptor activity-modifying proteins. CGRP is selective for CLR/ receptor activity modifying protein (RAMP)1, AM for CLR/RAMP2 and -3, and IMD acts at both CGRP and AM receptors. In a model of pressure overload induced by inhibition of nitric-oxide synthase, up-regulation of AM was observed previously in cardiomyocytes demonstrating a hypertrophic phenotype. The current objective was to examine the effects of blood pressure reduction on cardiomyocyte expression of AM and IMD and their receptor components. N -nitro-L-arginine methyl ester (L-NAME) (35 mg/ kg/day) was administered to rats for 8 weeks, with or without concurrent administration of hydralazine (50 mg/kg/day) and hydrochlorothiazide (7.5 mg/kg/day). In left ventricular cardiomyocytes from L-NAME-treated rats, increases (-fold) in mRNA expression were 1.6 (preproAM), 8.4 (preproIMD), 3.4 (CLR), 4.1 (RAMP1), 2.8 (RAMP2), and 4.4 (RAMP3). Hydralazine/hydrochlorothiazide normalized systolic blood pressure (BP) and abolished mRNA up-regulation of hypertrophic markers sk-␣-actin and BNP and of preproAM, CLR, RAMP2, and RAMP3 but did not normalize cardiomyocyte width nor preproIMD or RAMP1 mRNA expression. The robust increase in IMD expression indicates an important role for this peptide in the cardiac pathology of this model but, unlike AM, IMD is not associated with pressure overload upon the myocardium. The concordance of IMD and RAMP1 up-regulation indicates a CGRP-type receptor action; considering also a lack of response to BP reduction, IMD may, like CGRP, have an antiischemic function.

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Regulation of cardiac adrenomedullin-mRNA in different stages of experimental heart failure

Cited by 15 publications

References 22 publications

Adrenomedullin in Heart Failure

Adrenomedullin in Heart Failure

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

Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension

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