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

Sarigianni, Maria; Mikhailidis, Dimitri P.; Kaloyianni, Martha; Koliakos, George; Paletas, Konstantinos

doi:10.2174/1874192401004010181

Cited by 11 publications

(5 citation statements)

References 60 publications

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“…One was found on chromosome 1 in the body of the SLC9A1 (also known as NHE-1) gene, which codes for an integral membrane ion transporter involved in intracellular pH maintenance. SLC9A1 has been shown to be required for the increased adhesion, migration, and phagocytosis of oxidized LDL seen in monocytes in response to stimuli including leptin, adrenaline, and hyperglycemia [49]. Another region discovered was on chromosome 19 near the transcription start site (TSS) of SLC1A5, which codes for a neutral amino acid transporter.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

et al. 2019

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Background Epigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk. However, the direction of causation for these associations is not always clear, and investigations to-date have often failed to replicate at the level of individual loci. Methods Here, we undertook module- and region-based DNA methylation analyses of incident CVD in the Women’s Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. We applied weighted gene correlation network analysis (WGCNA) and the Comb-p algorithm to find methylation modules and regions associated with incident CVD in the WHI dataset. Results We discovered two modules whose activation correlated with CVD risk and replicated across cohorts. One of these modules was enriched for development-related processes and overlaps strongly with epigenetic aging sites. For the other, we showed preliminary evidence for monocyte-specific effects and statistical links to cumulative exposure to traditional cardiovascular risk factors. Additionally, we found three regions (associated with the genes SLC9A1, SLC1A5, and TNRC6C) whose methylation associates with CVD risk. Conclusions In sum, we present several epigenetic associations with incident CVD which reveal disease mechanisms related to development and monocyte biology. Furthermore, we show that epigenetic modules may act as a molecular readout of cumulative cardiovascular risk factor exposure, with implications for the improvement of clinical risk prediction.

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Section: Discussionmentioning

confidence: 99%

DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

et al. 2019

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“…Several models of cardiac hypertrophy involve signaling through phosphatidylinositide 3 kinase PI3K [9,20,36,37,74,82,102] which in turn participates in the regulation of NHE activity [51,86,87,91].…”

Section: Introductionmentioning

confidence: 99%

Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

et al. 2012

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Sustained increase of cardiac workload is known to trigger cardiac remodeling with eventual development of cardiac failure. Compelling evidence points to a critical role of enhanced cardiac Na(+)/H(+) exchanger (NHE1) activity in the underlying pathophysiology. The signaling triggering up-regulation of NHE1 remained, however, ill defined. The present study explored the involvement of the serum- and glucocorticoid-inducible kinase Sgk1 in cardiac remodeling due to transverse aortic constriction (TAC). To this end, experiments were performed in gene targeted mice lacking functional Sgk1 (sgk1 (-/-)) and their wild-type controls (sgk1 (+/+)). Transcript levels have been determined by RT-PCR, cytosolic pH (pH( i )) utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, Na(+)/H(+) exchanger activity by the Na(+)-dependent realkalinization after an ammonium pulse, ejection fraction (%) utilizing cardiac cine magnetic resonance imaging and cardiac glucose uptake by PET imaging. As a result, TAC increased the mRNA expression of Sgk1 in sgk1 (+/+) mice, paralleled by an increase in Nhe1 transcript levels as well as Na(+)/H(+) exchanger activity, all effects virtually abrogated in sgk1 (-/-) mice. In sgk1 (+/+) mice, TAC induced a decrease in Pgc1a mRNA expression, while Spp1 mRNA expression was increased, both effects diminished in the sgk1 (-/-) mice. TAC was followed by a significant increase of heart and lung weight in sgk1 (+/+) mice, an effect significantly blunted in sgk1 (-/-) mice. TAC increased the transcript levels of Anp and Bnp, effects again significantly blunted in sgk1 (-/-) mice. TAC increased transcript levels of Collagen I and III as well as Ctgf mRNA and CTGF protein abundance, effects significantly blunted in sgk1 (-/-) mice. TAC further decreased the ejection fraction in sgk1 (+/+) mice, an effect again attenuated in sgk1 (-/-) mice. Also, cardiac FDG-glucose uptake was increased to a larger extent in sgk1 (+/+) mice than in sgk1 (-/-) mice after TAC. These observations point to an important role for SGK1 in cardiac remodeling and development of heart failure following an excessive work load.

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“…However, the function of NHE1 is not restricted to pHi homeostasis but seems to play a key role in the signal pathway of modulating the proliferation, differentiation and so on [9,10]. Our previous studies have shown for the first time that AGEs via RAGE caused a rapid and sustained activation of NHE1, leading to VSMC proliferation [11].…”

Section: Introductionmentioning

confidence: 99%

Cariporide, a Specific Na<sup>+</sup>/H<sup>+</sup> Exchanger 1 Blocker, Inhibits Neointimal Proliferation Induced by Advanced Glycation End Products in a Balloon Injury Rat Model

Wu¹,

Yang

Liu

et al. 2013

Pharmacology

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Aims: The association between diabetes and neointimal expansion after vascular injury has been attributed to the accumulation of advanced glycation end products (AGEs). Here we investigated the inhibitory effect of cariporide, a specific Na⁺/H⁺ exchanger 1 blocker, on neointimal proliferation induced by AGEs in a balloon injury model. Methods: Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP) was monitored by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. The level of reactive oxygen species (ROS) was determined by specific fluorescent probe. The phosphorylation of the nuclear factor-ĸB (NF-ĸB) system was studied by Western blot. Results: Cariporide significantly suppressed AGE-induced neointimal hyperplasia, vascular smooth muscle cell (VSMC) proliferation, COX-2, MMP-2 and MMP-9 expression. In addition, cariporide decreased AGE-induced ROS, malondiadehyde level and increased the superoxide dismutase and glutathione peroxidase activity. We also found that cariporide blocked AGE-induced NF-ĸB activation and inhibitor-ĸB degradation. Conclusions: The results indicated that cariporide inhibited AGE-induced neointimal formation by suppressing the VSMC proliferation and the up-regulation of COX-2, MMP-2, MMP-9 via inhibiting ROS and NF-ĸB activation.

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

Cited by 11 publications

References 60 publications

DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

Cariporide, a Specific Na<sup>+</sup>/H<sup>+</sup> Exchanger 1 Blocker, Inhibits Neointimal Proliferation Induced by Advanced Glycation End Products in a Balloon Injury Rat Model

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