Stimulation of Na+H+ antiport activity by epidermal growth factor and insulin occurs without activation of protein kinase C

Vara, F

doi:10.1016/0006-291x(85)90466-8

Cited by 107 publications

(20 citation statements)

References 16 publications

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“…Moreover, H-ras p21 microinjection is associated with a rapid rise in intracellular pH (6). Evidence that this pH change is mediated by the amiloride-sensitive Na+-H+ antiporter, known to be activated by PKC (13), further supports the conclusion that PKC is activated early in response to H-ras p21. Thus, our present findings, in concert with these previous studies, support a model in which PKC is activated in response to the H-ras oncogene product and plays an important role in mediating its mitogenic action.…”

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confidence: 70%

Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product.

et al. 1987

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Nature [London] 324:375-377, 1986). Our present studies demonstrate that the mitogenic activity of the H-ras oncogene in H-ras p21-microinjected quiescent cells is markedly reduced under conditions in which PKC is downregulated by chronic phorbol ester treatment. The ability to reconstitute the mitogenic response upon microinjection of both H-ras p21 and PKC implies involvement of functional PKC in the mitogenic activity of the H-ras oncogene product.

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confidence: 70%

Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product.

et al. 1987

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“…All of the reported agonist and antagonist properties of PMA have been shown to be inhibited by protein kinase C inhibitors [23,26,27]. There are two possible explanations for this result.…”

Section: Methodsmentioning

confidence: 93%

Cell alkalinization is not necessary and increased sodium influx is not sufficient for stimulated superoxide production

et al. 1986

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Preincubation of rabbit neutrophils for 5 min with the protein kinase C inhibitor H7 causes inhibition of the rise in intracellular pH but not the increase in Na+ influx or stimulated oxidative burst produced by the chemotactic factor formyl-methionyl-leucyl-phenylalanine.On the other hand, the stimulated superoxide production, but not the increase in Nat influx produced by phorbol 12-myristate 13-acetate, is inhibited by H7. The effect is more pronounced on the rate than the extent of the stimulated superoxide release. Furthermore, cell acidification produced by the phorbol ester but not by the chemotactic factor is decreased in the presence of H7. These results suggest that (i) most of the stimulated Na+ influx is not coupled to H+ efflux, (ii) in the case of the chemoattractant, the rise in intracellular pH is not necessary for stimulated superoxide production, (iii) the increase in Nat influx, in the case of the phorbol ester, is not sufficient for the stimulation of the oxidative burst, and (iv) the sources of the H+ responsible for the stimulated pH drop are the various metabolic activities of the cell, including NADPH oxidation and activation of the hexose monophosphate shunt. H7IonJIux Protein kinase C &peroxide

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“…This function seems to play an important role in regulating vascular smooth muscle cell proliferation (29). A wide range of mitogenic factors can stimulate cell proliferation and activate NHE (30), including platelet-derived growth factor (PDGF) (9,31) and epidermal growth factor (EGF) (9,32,33). PDGF is one of the growth factors released by endothelial cells exposed to hypoxia (6,23).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the NHE1 Gene Prevents Hypoxia-induced Pulmonary Hypertension and Vascular Remodeling

Quinn

Garg

et al. 2008

Am J Respir Crit Care Med

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Rationale: Our previous studies found that Na 1 /H 1 exchanger (NHE) activity played an essential role in pulmonary artery smooth muscle cell (PASMC) proliferation and in the development of hypoxiainduced pulmonary hypertension and vascular remodeling. Other investigators recently observed increased expression of the NHE isoform 1 (NHE1) gene in rodents with pulmonary hypertension induced by hypoxia. However, a causal role for the NHE1 gene in pulmonary hypertension has not been determined. Objectives: To determine the causal role of the NHE1 gene in pulmonary hypertension and vascular remodeling. Methods: We used NHE1-null mice to define the role of the NHE1 gene in the development of pulmonary hypertension and remodeling induced by hypoxia and to delineate the NHE1 regulatory pathway. Measurements and Main Results: After 2 weeks of exposure to hypoxia, in contrast to wild-type hypoxic littermates, there was no significant increase in right ventricular systolic pressure, in the ratio of right ventricular to left ventricular plus septal weight [RV/(LV 1 S)], or in medial wall thickness of the pulmonary arterioles in homozygous mice (NHE1 2/2 ). There was a significant decrease in Rho kinase (ROCK1 and ROCK2) expression, accompanied by an increase in p27 expression in NHE1 2/2 mice. Conclusions: Our study demonstrated that deficiency of the NHE1 gene prevented the development of hypoxia-induced pulmonary hypertension and vascular remodeling in mice and revealed a novel regulatory pathway associated with NHE1 signaling. Keywords: Na 1 /H 1 exchanger isoform 1; pulmonary hypertension; vascular remodeling; hypoxia; mouseThe Na 1 /H 1 exchanger (NHE) expressed in many mammalian cell types is a protein localized to the plasma and the mitochondrial inner membrane (1). The function of NHE is to regulate intracellular pH and cell volume by extruding H 1 from and taking up Na 1 into cells (2). Since NHE was first analyzed in 1976 (3) and the first NHE cDNA was cloned in 1989 (4), nine NHE isoforms have been identified and cloned (2), of which NHE isoform 1 (NHE1) is ubiquitously expressed.Pulmonary hypertension caused by many chronic lung diseases associated with prolonged hypoxia can result in right ventricular hypertrophy and heart failure (5). An important pathological feature of pulmonary hypertension is increased medial thickening of the pulmonary artery resulting from hypertrophy and hyperplasia of the pulmonary artery smooth muscle cells (PASMCs) (6, 7). In previous studies, we reported that NHE activity played a significant role in regulation of intracellular pH in PASMCs (8) and found that the inhibition of NHE activity was related to the inhibition of bovine PASMC proliferation induced by growth factors (9, 10). We also found that inhibition of NHE activity significantly reduced pulmonary hypertension and vascular remodeling induced by chronic hypoxia in rats (11). Our studies suggested that NHE activity might play an important role in development of pulmonary hypertension and vascular remodeling.Recently, incre...

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Stimulation of Na+H+ antiport activity by epidermal growth factor and insulin occurs without activation of protein kinase C

Cited by 107 publications

References 16 publications

Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product.

Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product.

Cell alkalinization is not necessary and increased sodium influx is not sufficient for stimulated superoxide production

Deficiency of the NHE1 Gene Prevents Hypoxia-induced Pulmonary Hypertension and Vascular Remodeling

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