C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

Oller, Jorge; Alfranca, Arántzazu; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Ángel Luis; Campanero, Miguel R.; Redondo, Juan Miguel

doi:10.1128/mcb.00494-15

Cited by 19 publications

(14 citation statements)

References 58 publications

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“…Finally, adventitial expression of Annexin-A2 is interesting as we have previously shown that fibrosis in the 2K1C can first be detected in this specific localization of Annexin-A2 (46). This is consistent with earlier findings that NFAT activation regulates ADAMTS-1 in vascular remodeling (38) and with our previous data showing ADAMTS-1 upregulation in chronic hypertensive damage (45). Surprisingly, although mRNA-independent elevation of NFAT5 protein level following AT1R activation correlates with Annexin-A2 binding, AT1R inhibition by losartan caused increased levels of both NFAT5 mRNA and protein.…”

Section: F107supporting

confidence: 90%

NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

Fähling

Paliege

Jönsson

et al. 2019

American Journal of Physiology-Renal Physiology

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The aim was to identify new targets that regulate gene expression at the posttranscriptional level in angiotensin II (ANGII)-mediated hypertension. Heparin affinity chromatography was used to enrich nucleic acid-binding proteins from kidneys of two-kidney, one-clip (2K1C) hypertensive Wistar rats. The experiment was repeated with 14-day ANGII infusion using Alzet osmotic mini pumps, with or without ANGII receptor AT1a inhibition using losartan in the drinking water. Mean arterial pressure increased after 2K1C or ANGII infusion and was inhibited with losartan. Heparin affinity chromatography and mass spectrometry were used to identify Annexin-A2 (ANXA2) as having differential nucleic acid-binding activity. Total Annexin-A2 protein expression was unchanged, whereas nucleic acid-binding activity was increased in both kidneys of 2K1C and after ANGII infusion through AT1a stimulation. Costaining of Annexin-A2 with α-smooth muscle actin and aquaporin 2 showed prominent expression in the endothelia of larger arteries and the cells of the inner medullary collecting duct. The nuclear factor of activated T cells (NFAT) transcription factor was identified as a likely Annexin-A2 target using enrichment analysis on a 2K1C microarray data set and identifying several binding sites in the regulatory region of the mRNA. Expression analysis showed that ANGII increases NFAT5 protein but not mRNA level and, thus, indicated that NFAT5 is regulated by posttranscriptional regulation, which correlates with activation of the RNA-binding protein Annexin-A2. In conclusion, we show that ANGII increases Annexin-A2 nucleic acid-binding activity that correlates with elevated protein levels of the NFAT5 transcription factor. NFAT signaling appears to be a major contributor to renal gene regulation in high-renin states.

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Section: F107supporting

confidence: 90%

NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

Fähling

Paliege

Jönsson

et al. 2019

American Journal of Physiology-Renal Physiology

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“…At 14 to 15 week of age, male wild‐type mice were randomly assigned to three groups, and they received either Ang II (400 ng/kg/min) (n = 9) or Ang II with losartan (10 mg/kg/min) (n = 8) or saline (n = 8) for 2 weeks via subcutaneous implantation of osmotic mini‐pumps (model 1004, ALZET Corp, Palo Alto, CA). The concentration of losartan was determined based on previous papers 44‐46 . After 2 weeks of infusion, tissues were excised, weighed, and subjected to further analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The concentration of losartan was determined based on previous papers. [44][45][46] After 2 weeks of infusion, tissues were excised, weighed, and subjected to further analysis. Blood pressure (BP) was measured before and after the administration of reagents using the tail-cuff method (Softron Co, Tokyo, Japan).…”

Section: Experimental Animals and Protocolsmentioning

confidence: 99%

A pressor dose of angiotensin II has no influence on the angiotensin‐converting enzyme 2 and other molecules associated with SARS‐CoV‐2 infection in mice

et al. 2021

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In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cellsurface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

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“…To isolate and culture primary mouse vascular smooth muscle cells (vSMC), aortas were dissected and the adventitia was removed with forceps 21 . Tissue was digested with a solution of collagenase and elastase until a single-cell suspension was obtained.…”

Section: Methodsmentioning

confidence: 99%

Conditional deletion of Rcan1 predisposes to hypertension-mediated intramural hematoma and subsequent aneurysm and aortic rupture

et al. 2018

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Aortic intramural hematoma (IMH) can evolve toward reabsorption, dissection or aneurysm. Hypertension is the most common predisposing factor in IMH and aneurysm patients, and the hypertensive mediator angiotensin-II induces both in mice. We have previously shown that constitutive deletion of Rcan1 isoforms prevents Angiotensin II-induced aneurysm in mice. Here we generate mice conditionally lacking each isoform or all isoforms in vascular smooth muscle cells, endothelial cells, or ubiquitously, to determine the contribution to aneurysm development of Rcan1 isoforms in vascular cells. Surprisingly, conditional Rcan1 deletion in either vascular cell-type induces a hypercontractile phenotype and aortic medial layer disorganization, predisposing to hypertension-mediated aortic rupture, IMH, and aneurysm. These processes are blocked by ROCK inhibition. We find that Rcan1 associates with GSK-3β, whose inhibition decreases myosin activation. Our results identify potential therapeutic targets for intervention in IMH and aneurysm and call for caution when interpreting phenotypes of constitutively and inducibly deficient mice.

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C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

Cited by 19 publications

References 58 publications

NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

A pressor dose of angiotensin II has no influence on the angiotensin‐converting enzyme 2 and other molecules associated with SARS‐CoV‐2 infection in mice

Conditional deletion of Rcan1 predisposes to hypertension-mediated intramural hematoma and subsequent aneurysm and aortic rupture

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