A major role for
            <scp>RCAN</scp>
            1 in atherosclerosis progression

Esteban, Vanesa; Villahoz, Silvia; Escolano, Amelia; Urso, Katia; Alfranca, Arántzazu; Rodrı́guez, Cristina; Sánchez, Susana A.; Osawa, Tsuyoshi; Andrés, Vicente; Martı́nez-González, José; Minami, Takashi; Redondo, Juan Miguel; Campanero, Miguel R.

doi:10.1002/emmm.201302842

Cited by 34 publications

(36 citation statements)

References 57 publications

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“…CTRP13 reduced macrophage content in the lesion, not vascular SMCs, and inhibited cholesterol influx, not efflux in macrophages, to suppress foam-cell formation. The lipid-laden foam cells do not leave the lesion after clearing the lipids (28). Thus, their normal biologic role is perturbed, and macrophages trapped in the arterial intima provoke an inflammatory response at the local site (29).…”

Section: Discussionmentioning

confidence: 99%

CTRP13 inhibits atherosclerosis via autophagy‐lysosome‐dependent degradation of CD36

Wang

Liang

et al. 2018

FASEB j.

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C1q/tumor necrosis factor-related protein 13 (CTRP13) is a secreted adipokine that can ameliorate abnormal glucose and lipid metabolism. However, the functional role of CTRP13 in the development of atherosclerotic plaques has yet to be described. In this study, we collected blood samples from patients of coronary artery diseases and apolipoprotein E (ApoE) mice that were fed a Western diet for 12 wk to induce atherosclerosis and found that serum CTRP13 level was decreased. En face staining of aortas and aortic sinus in ApoE mice showed that ectopic CTRP13 infusion in vivo dramatically decreased lesion areas, as well as reduced inflammatory responses with less macrophage content. In primary peritoneal macrophages in vitro, CTRP13 supplement reduced oxidized LDL uptake, foam-cell formation, and trapping, together with the suppressed cluster of differentiation 36 (CD36) protein levels. Reduced CD36 protein level was attributed to the autophagy-lysosome-dependent degradation of CD36 at the post-transcriptional level. The blocking of autophagy-lysosome induction could increase CD36 protein level, foam-cell formation, and migration, thus abolishing the protective effects of CTRP13 on atherosclerosis. In summary, these findings define CTRP13 as a novel approach for preventing atherosclerotic plaque formation via modulation of lipid uptake and foam-cell migration.-Wang, C., Xu, W., Liang, M., Huang, D., Huang, K. CTRP13 inhibits atherosclerosis via autophagy-lysosome-dependent degradation of CD36.

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Section: Discussionmentioning

confidence: 99%

CTRP13 inhibits atherosclerosis via autophagy‐lysosome‐dependent degradation of CD36

Wang

Liang

et al. 2018

FASEB j.

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“…However, calcineurin also activates receptor for activated protein kinase C1 (RACK1), which has been implicated in regulating cell migration through binding to an array of signalling proteins. Endothelial cells constitutively express RCAN1 at a basal level ( Holmes et al, 2010 ; Méndez-Barbero et al, 2013 ). Thus, depleting NFATc2 could reduce basal levels of RCAN1, subsequently leading to increased endothelial cell migration through attenuated calcineurin-stimulated RACK1 signalling.…”

Section: Discussionmentioning

confidence: 99%

VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration

et al. 2015

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Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology such as cell migration, proliferation, tubulogenesis and cell-cell interactions. Numerous isoforms of VEGF-A exist but their physiological significance is unclear. Here we evaluated two different VEGF-A isoforms and discovered differential regulation of cytosolic calcium ion flux, transcription factor localisation and endothelial cell response. Analysis of VEGF-A isoform-specific stimulation of VEGFR2-dependent signal transduction revealed differential capabilities for isoform activation of multiple signal transduction pathways. VEGF-A165 treatment promoted increased phospholipase Cγ1 phosphorylation, which was proportional to the subsequent rise in cytosolic calcium ions, in comparison to cells treated with VEGF-A121. A major consequence of this VEGF-A isoform-specific calcium ion flux in endothelial cells is differential dephosphorylation and subsequent nuclear translocation of the transcription factor NFATc2. Using reverse genetics, we discovered that NFATc2 is functionally required for VEGF-A-stimulated endothelial cell migration but not tubulogenesis. This work presents a new mechanism for understanding how VEGF-A isoforms program complex cellular outputs by converting signal transduction pathways into transcription factor redistribution to the nucleus, as well as defining a novel role for NFATc2 in regulating the endothelial cell response.

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“…Interestingly, calcineurindependent expression of RCAN1.4 in other cell types has been linked to pathological vascular wall remodeling 34 and atherosclerosis progression. 35 Hence, the potential role of PMCA4 in the modulation of vascular pathologies linked to RCAN1.4 aberrant expression deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

Plasma Membrane Calcium ATPase Isoform 4 Inhibits Vascular Endothelial Growth Factor–Mediated Angiogenesis Through Interaction With Calcineurin

Baggott

Alfranca

López-Maderuelo

et al. 2014

ATVB

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Objective— Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF, activation of the calcineurin/nuclear factor of activated T cells (NFAT) signaling axis has emerged as a critical mediator of angiogenic processes. We and others previously reported a novel role for the plasma membrane calcium ATPase (PMCA) as an endogenous inhibitor of the calcineurin/NFAT pathway, via interaction with calcineurin, in cardiomyocytes and breast cancer cells. However, the functional significance of the PMCA/calcineurin interaction in endothelial pathophysiology has not been addressed thus far. Approach and Results— Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and to a significant reduction in the subsequent expression of the NFAT-dependent, VEGF-activated, proangiogenic genes RCAN1.4 and Cox-2 . PMCA4-dependent inhibition of calcineurin signaling translates into a reduction in endothelial cell motility and blood vessel formation that ultimately impairs in vivo angiogenesis by VEGF. Conclusions— Given the importance of the calcineurin/NFAT pathway in the regulation of pathological angiogenesis, targeted modulation of PMCA4 functionality might open novel therapeutic avenues to promote or attenuate new vessel formation in diseases that occur with angiogenesis.

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A major role for RCAN 1 in atherosclerosis progression

Cited by 34 publications

References 57 publications

CTRP13 inhibits atherosclerosis via autophagy‐lysosome‐dependent degradation of CD36

CTRP13 inhibits atherosclerosis via autophagy‐lysosome‐dependent degradation of CD36

VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration

Plasma Membrane Calcium ATPase Isoform 4 Inhibits Vascular Endothelial Growth Factor–Mediated Angiogenesis Through Interaction With Calcineurin

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