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Activation of the AT1R/HIF-1 α /ACE axis mediates angiotensin II-induced VEGF synthesis in mesenchymal stem cells.

Liu C, Zhang JW, Hu L, Song YC, Zhou L, Fan Y, Zhu HY, Wang Y, Li QP - Biomed Res Int (2014)

Bottom Line: We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R).The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II.We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

View Article: PubMed Central - PubMed

Affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.

ABSTRACT
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

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Related in: MedlinePlus

Ang II degradation and formation. Ang II concentration was determined by radioimmunoassay. Exogenous Ang II (100 nM) was added to the culture medium at time 0. Concentrations were determined at 1, 3, 6, 9, 15, 21, 27, and 33 h. n = 3. *P < 0.05, 21 h versus 3, 6, 9, 15 h. The concentration of Ang II in untreated MSC culture medium was also tested as the physiological concentration. n = 3.
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fig4: Ang II degradation and formation. Ang II concentration was determined by radioimmunoassay. Exogenous Ang II (100 nM) was added to the culture medium at time 0. Concentrations were determined at 1, 3, 6, 9, 15, 21, 27, and 33 h. n = 3. *P < 0.05, 21 h versus 3, 6, 9, 15 h. The concentration of Ang II in untreated MSC culture medium was also tested as the physiological concentration. n = 3.

Mentions: The cleavage of exogenously added Ang II and the formation of endogenous Ang II in MSC culture media were determined by radioimmunoassay. Exogenous Ang II (100 nM) was added. The Ang II concentration was reduced to 1106 ± 40.48 pM after 1 h and continued to drop to 42.45 ± 4.26 pM after 3 h (Figure 4). However, the Ang II concentration increased significantly from 4 h (42.45 ± 4.26 pM) to 21 h (89.12 ± 4.02 pM) and then decreased at 27 h (50.78 ± 8.90 pM). The Ang II concentration tended to increase again from 28 to 33 h. The Ang II level of untreated MSCs, that is, the physiological concentration, was 41.05 ± 2.83 pM (Figure 4).


Activation of the AT1R/HIF-1 α /ACE axis mediates angiotensin II-induced VEGF synthesis in mesenchymal stem cells.

Liu C, Zhang JW, Hu L, Song YC, Zhou L, Fan Y, Zhu HY, Wang Y, Li QP - Biomed Res Int (2014)

Ang II degradation and formation. Ang II concentration was determined by radioimmunoassay. Exogenous Ang II (100 nM) was added to the culture medium at time 0. Concentrations were determined at 1, 3, 6, 9, 15, 21, 27, and 33 h. n = 3. *P < 0.05, 21 h versus 3, 6, 9, 15 h. The concentration of Ang II in untreated MSC culture medium was also tested as the physiological concentration. n = 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4221905&req=5

fig4: Ang II degradation and formation. Ang II concentration was determined by radioimmunoassay. Exogenous Ang II (100 nM) was added to the culture medium at time 0. Concentrations were determined at 1, 3, 6, 9, 15, 21, 27, and 33 h. n = 3. *P < 0.05, 21 h versus 3, 6, 9, 15 h. The concentration of Ang II in untreated MSC culture medium was also tested as the physiological concentration. n = 3.
Mentions: The cleavage of exogenously added Ang II and the formation of endogenous Ang II in MSC culture media were determined by radioimmunoassay. Exogenous Ang II (100 nM) was added. The Ang II concentration was reduced to 1106 ± 40.48 pM after 1 h and continued to drop to 42.45 ± 4.26 pM after 3 h (Figure 4). However, the Ang II concentration increased significantly from 4 h (42.45 ± 4.26 pM) to 21 h (89.12 ± 4.02 pM) and then decreased at 27 h (50.78 ± 8.90 pM). The Ang II concentration tended to increase again from 28 to 33 h. The Ang II level of untreated MSCs, that is, the physiological concentration, was 41.05 ± 2.83 pM (Figure 4).

Bottom Line: We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R).The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II.We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

View Article: PubMed Central - PubMed

Affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.

ABSTRACT
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

Show MeSH
Related in: MedlinePlus