Hepatocyte cytoskeleton during ischemia and reperfusion - influence of ANP-mediated p38 MAPK activation

Keller, Melanie; Gerbes, Alexander L.; Kulhanek-Heinze, Stefanie; Gerwig, Tobias; Grützner, Uwe; Rooijen, Nico van; Vollmar, Angelika M.; Kiemer, Alexandra K.

doi:10.3748/wjg.v11.i47.7418

Cited by 15 publications

(14 citation statements)

References 51 publications

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“…p38 MAPK mediates proliferation and migration in human ECs induced by mitogens such as VEGF-A (40). In line with our observations, a selective induction of phospho-p38 (and not of phospho-ERK1/2) by NPs has been observed in other tissues (41). Taken together, our data suggest that activation of VASP and of p38 MAPK cooperate in the NP/GC-A-dependent stimulation of processes required for angiogenesis, such as endothelial proliferation and migration.…”

Section: Figuresupporting

confidence: 80%

The natriuretic peptide/guanylyl cyclase–A system functions as a stress-responsive regulator of angiogenesis in mice

Kühn¹,

Völker²,

Schwarz³

et al. 2009

J. Clin. Invest.

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Cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) modulate blood pressure and volume by activation of the receptor guanylyl cyclase-A (GC-A) and subsequent intracellular cGMP formation.Here we report what we believe to be a novel function of these peptides as paracrine regulators of vascular regeneration. In mice with systemic deletion of the GC-A gene, vascular regeneration in response to critical hind limb ischemia was severely impaired. Similar attenuation of ischemic angiogenesis was observed in mice with conditional, endothelial cell-restricted GC-A deletion (here termed EC GC-A KO mice). In contrast, smooth muscle cell-restricted GC-A ablation did not affect ischemic neovascularization. Immunohistochemistry and RT-PCR revealed BNP expression in activated satellite cells within the ischemic muscle, suggesting that local BNP elicits protective endothelial effects. Since within the heart, BNP is mainly induced in cardiomyocytes by mechanical load, we investigated whether the natriuretic peptide/GC-A system also regulates angiogenesis accompanying load-induced cardiac hypertrophy. EC GC-A KO hearts showed diminished angiogenesis, mild fibrosis, and diastolic dysfunction. In vitro BNP/GC-A stimulated proliferation and migration of cultured microvascular endothelia by activating cGMP-dependent protein kinase I and phosphorylating vasodilatorstimulated phosphoprotein and p38 MAPK. We therefore conclude that BNP, produced by activated satellite cells within ischemic skeletal muscle or by cardiomyocytes in response to pressure load, regulates the regeneration of neighboring endothelia via GC-A. This paracrine communication might be critically involved in coordinating muscle regeneration/hypertrophy and angiogenesis.

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Section: Figuresupporting

confidence: 80%

The natriuretic peptide/guanylyl cyclase–A system functions as a stress-responsive regulator of angiogenesis in mice

Kühn¹,

Völker²,

Schwarz³

et al. 2009

J. Clin. Invest.

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“…Recently, BNP has been reported to provoke in vitro in cultured microvascular endothelia a mild but significant increase in the levels of phosphorylated p38 MAPK within 15 minutes. 34 In addition, ANP increases p38 MAPK activity in vivo within 20 minutes in the liver, 49 whereas in human umbilical vein endothelial cells, ANP induces inhibition of p38 MAPK through activation of its upstream regulator, the MAPK phosphatase-1. 50 The reason for these discrepant findings may be the differences in experimental settings, and clearly more studies are necessary to better understand the role of p38 MAPK in mediating the effects of the NPs on cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

Moilanen

Rysä

Mustonen

et al. 2011

Circ: Heart Failure

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Background-B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions mainly by ventricular myocytes. It has natriuretic, diuretic, blood pressure-lowering, and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases. In the present study, we used BNP gene transfer to examine functional and structural effects of BNP on left ventricular (LV) remodeling. Methods and Results-Human BNP was overexpressed by using adenovirus-mediated gene delivery in normal rat hearts and in hearts during the remodeling process after infarction and in an experimental model of angiotensin II-mediated hypertension. In healthy hearts, BNP gene delivery into the anterior wall of the LV decreased myocardial fibrosis (PϽ0.01, nϭ7 to 8) and increased capillary density (PϽ0.05, nϭ7 to 8) associated with a 7.3-fold increase in LV BNP peptide levels. Overexpression of BNP improved LV fractional shortening by 22% (PϽ0.05, nϭ6 to 7) and ejection fraction by 19% (PϽ0.05, nϭ6 to 7) after infarction. The favorable effect of BNP gene delivery on cardiac function after infarction was associated with normalization of cardiac sarcoplasmic reticulum Ca 2ϩ -ATPase expression and phospholamban Thr17-phosphorylation. BNP gene delivery also improved fractional shortening and ejection fraction in angiotensin II-mediated hypertension as well as decreased myocardial fibrosis and LV collagen III mRNA levels but had no effect on angiogenesis or Ca 2ϩ -ATPase expression and phospholamban phosphorylation. Conclusions-Local intramyocardial BNP gene delivery improves cardiac function and attenuates adverse postinfarctionand angiotensin II-induced remodeling. These results also indicate that myocardial BNP has pleiotropic, contextdependent, favorable actions on cardiac function and suggest that BNP acts locally as a key mechanical load-activated regulator of angiogenesis and fibrosis. (Circ Heart Fail. 2011;4:483-495.)Key Words: B-type natriuretic peptide Ⅲ gene therapy Ⅲ heart failure Ⅲ myocardial infarction Ⅲ angiogenesis Ⅲ fibrosis H eart failure (HF) is one of the most common causes of cardiovascular morbidity and mortality, and its prevalence is rapidly increasing as the mean age of the population advances. 1 The major cause of systolic HF is coronary artery disease, whereas diastolic HF (HF with preserved ejection fraction [EF]) is more common in patients with hypertension. 2,3 Worsening of chronic systolic or diastolic dysfunction is the most common form of acute HF, accounting for a substantial number of hospitalizations with a poor prognosis. 4 A number of drugs, particularly ␤-blockers and drugs acting on the renin-angiotensin-aldosterone system, have been shown to improve survival in patients who have left ventricular (LV) systolic dysfunction. 2,3 However, identifying appropriate treatments for patients who have HF with preserved EF or acute HF has been a daunting task. [2][3][4] Clinical Perspective on p 495Atrial and B-type natriuretic peptides (ANP and BNP, re...

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“…Deletion of GC-A results in cardiac hypertrophy and is associated with increased pro-inflammatory cytokine expression (12). Treatment with atrial natriuretic peptide (ANP), a GC-A activating ligand, diminishes TNFα, IL-1β, and inducible nitric-oxide synthase activity in hepatocytes and macrophages (13–16). Conversely, within the specific context of ischemia/reperfusion injury, the presence of GC-A seems to drive tissue damage and inflammation (17).…”

Section: Introductionmentioning

confidence: 99%

Murine Guanylate Cyclase C Regulates Colonic Injury and Inflammation

Steinbrecher

Harmel‐Laws

Garin-Laflam

et al. 2011

The Journal of Immunology

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Guanylate cyclase C (GUCY2C or GC-C) and its ligands, guanylin (GUCA2A or Gn) and uroguanylin (GUCA2B or Ugn), are expressed in intestinal epithelial cells (IECs) and regulate ion secretion, intestinal barrier function, and epithelial monolayer homeostasis via cGMP-dependent signaling pathways. The aim of this study was to determine if GC-C and its ligands direct the course of intestinal inflammation. Here, we show that DSS-induced clinical disease and histological damage to the colonic mucosa were significantly less severe in GC-C−/− mice and moderately reduced in Gn−/− animals. Relative to wildtype controls, GC-C−/− and Gn−/− mice had reduced apoptosis and increased proliferation of IECs during DSS colitis. Basal and DSS-induced production of resistin-like molecule β (RELMβ) was substantially diminished in GC-C−/− mice. RELMβ is thought to stimulate cytokine production in macrophages in this disease model and, consistent with this, TNFα and IFNγ production was minimal in GC-C−/− animals. RELMβ and cytokine levels were similar to wildtype in Gn−/− mice, however. Colonic instillation of recombinant RELMβ by enema into GC-C−/− mice restores sensitivity to DSS-mediated mucosal injury. These findings demonstrate a novel role for GC-C signaling in facilitating mucosal wounding and inflammation and further suggest that this may be mediated, in part, through control of RELMβ production.

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Hepatocyte cytoskeleton during ischemia and reperfusion - influence of ANP-mediated p38 MAPK activation

Abstract: This study reveals that ANP-mediated p38 MAPK activation leads to changes in hepatocyte cytoskeleton involving an elevation of phosphorylated Hsp27 and thereby for the first time shows functional consequences of ANP-induced hepatic p38 MAPK activation.

Cited by 15 publications

References 51 publications

The natriuretic peptide/guanylyl cyclase–A system functions as a stress-responsive regulator of angiogenesis in mice

The natriuretic peptide/guanylyl cyclase–A system functions as a stress-responsive regulator of angiogenesis in mice

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

Murine Guanylate Cyclase C Regulates Colonic Injury and Inflammation

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