Involvement of Signaling Molecules on Na+/H+ Exchanger-1 Activity in Human Monocytes

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Abstract

Background:

Sodium/hydrogen exchanger-1 (NHE-1) contributes to maintaining intracellular pH (pHi). We assessed the effect of glucose, insulin, leptin and adrenaline on NHE-1 activity in human monocytes in vitro. These cells play a role in atherogenesis and disturbances in the hormones evaluated are associated with obesity and diabetes.

Methods and Results:

Monocytes were isolated from 16 healthy obese and 10 lean healthy subjects. NHE-1 activity was estimated by measuring pHi with a fluorescent dye. pHi was assessed pre- and post-incubation with glucose, insulin, leptin and adrenaline. Experiments were repeated after adding a NHE-1 inhibitor (cariporide) or an inhibitor of protein kinase C (PKC), nitric oxide synthase (NOS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, phosphoinositide 3-kinases (PI3K) or actin polymerization. Within the whole study population, glucose enhanced NHE-1 activity by a processes involving PKC, NOS, PI3K and actin polymerization (p = 0.0006 to 0.01). Insulin-mediated activation of NHE-1 (p = <0.0001 to 0.02) required the classical isoforms of PKC, NOS, NADPH oxidase and PI3K. Leptin increased NHE-1 activity (p = 0.0004 to 0.04) through the involvement of PKC and actin polymerization. Adrenaline activated NHE-1 (p = <0.0001 to 0.01) by a process involving the classical isoforms of PKC, NOS and actin polymerization. There were also some differences in responses when lean and obese subjects were compared. Incubation with cariporide attenuated the observed increase in NHE-1 activity.

Conclusions:

Selective inhibition of NHE-1 in monocytes could become a target for drug action in atherosclerotic vascular disease.

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Most cited references 61

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Caroline S. Fox, Sean Coady, Paul Sorlie … (2007)

Marked reductions in cardiovascular disease (CVD) morbidity and mortality have occurred in the United States over the last 50 years. We tested the hypothesis that the relative burden of CVD attributable to diabetes mellitus (DM) has increased over the past 5 decades. Participants aged 45 to 64 years from the Framingham Heart Study, who attended examinations in an "early" time period (1952 to 1974), were compared with those who attended examinations in a later time period (1975 to 1998). The risk of CVD events (n=133 among those with and 1093 among those without DM) attributable to DM in the 2 time periods was assessed with Cox proportional hazards models; population attributable risk of DM as a CVD risk factor was calculated for each time period. The age- and sex-adjusted hazard ratio for DM as a CVD risk factor was 3.0 (95% CI, 2.3 to 3.9) in the earlier time period and 2.5 (95% CI, 1.9 to 3.2) in the later time period. The population attributable risk for DM as a CVD risk factor increased from 5.4% (95% CI, 3.8% to 6.9%) in the earlier time period to 8.7% (95% CI, 5.9% to 11.4%) in the later time period (P for attributable risk ratio=0.04), although multivariable adjustment resulted in attenuation of these findings (P=0.12); most of these observations were found among men. The proportion of CVD attributable to DM has increased over the past 50 years in Framingham. These findings emphasize the need for increased efforts to prevent DM and to aggressively treat and control CVD risk factors among those with DM.

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Muscle sympathetic nerve activity (MSNA) is elevated in obese humans. However, the potential role of abdominal visceral fat as an important adipose tissue depot linking obesity to elevated MSNA has not been explored. Accordingly, we tested the hypothesis that MSNA would be increased in men (age=18 to 40 years, body mass index 0.05), total fat mass-matched (20.6+/-2.1 versus 20.8+/-2.4 kg, P>0.05) and abdominal subcutaneous fat-matched (230.6+/-24.9 versus 261.4+/-34.8 cm(2), P>0.05) peers with lower abdominal visceral fat levels (LAVF; n=13, visceral fat= 73.0+/-6.0 cm2). MSNA (microneurography), body composition (dual energy x-ray absorptiometry), and abdominal visceral and subcutaneous fat (computed tomography) were measured in 37 sedentary men across a wide range of adiposity. MSNA was approximately 55% higher in men with HAVF compared with men with LAVF (33+/-4 versus 21+/-2 bursts/min, P<0.05). Furthermore, MSNA was more closely associated with the level of abdominal visceral fat (r=0.65, P<0.05) than total fat mass (r=0.323, P<0.05) or abdominal subcutaneous fat (r=0.27, P=0.05). The relation between MSNA and abdominal visceral fat was independent of total body fat (r=0.61, P<0.05). The results of our study indicate that MSNA is elevated in men with visceral obesity. Our observations are consistent with the idea that abdominal visceral fat is an important adipose tissue depot linking obesity with sympathetic neural activation in humans. Furthermore, these findings may have important implications for understanding the increased risk of developing cardiovascular diseases in individuals with visceral obesity.

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Author and article information

Journal

Journal ID (nlm-ta): Open Cardiovasc Med J

Journal ID (publisher-id): TOCMJ

Title: The Open Cardiovascular Medicine Journal

Publisher: Bentham Open

ISSN (Electronic): 1874-1924

Publication date (Electronic): 28 September 2010

Publication date Collection: 2010

Volume: 4

Pages: 181-188

Affiliations

[1 ]Metabolic Diseases Unit, Second Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Greece

[2 ]Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital campus, University College London Medical School, University College London (UCL), London NW3 2QG, UK

[3 ]University of Oxford, The Tseu Medical Institute, Harris Manchester College, Oxford, United Kingdom

[4 ]Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, Greece

[5 ]Department of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Greece

Author notes

[* ]Address correspondence to this author at the 15 Ag. Sofias str, 54623, Thessaloniki, Greece; Tel: 00302310892751 Fax: 00302310992937 E-mail: paletas@ 123456med.auth.gr

[#]

The paper has not been presented orally in any professional meeting.

This paper is part of the 03ED29 research project, implemented within the framework of the “Reinforcement Programme of Human Research Manpower” (PENED) and cofinanced by National and European Community Funds (25% from the Greek Ministry of Development - General Secretariat of Research and Technology and 75% from the EU - European Social Fund).

Article

Publisher ID: TOCMJ-4-181

DOI: 10.2174/1874192401004010181

PMC ID: 3002055

PubMed ID: 21160910

SO-VID: f163089b-a922-4a72-83d1-44fd7cb0e3fb

License:

This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

History

Date received : 26 July 2010

Date revision received : 30 July 2010

Date accepted : 2 August 2010

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