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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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Interaction of HIF-1α with ACE in MSCs. (a) Real-time qPCR analysis of ACE mRNA level. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 12 h. n = 5, *P < 0.05. (b) Western blot analysis of ACE expression. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 6 h. n = 5, *P < 0.05. (c) Western blot analysis of HIF-1α. MSCs were pretreated with or without captopril (1 μM) for 1 h before they were exposed to Ang II (100 nM) for 12 h. n = 5, **P < 0.01.
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fig3: Interaction of HIF-1α with ACE in MSCs. (a) Real-time qPCR analysis of ACE mRNA level. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 12 h. n = 5, *P < 0.05. (b) Western blot analysis of ACE expression. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 6 h. n = 5, *P < 0.05. (c) Western blot analysis of HIF-1α. MSCs were pretreated with or without captopril (1 μM) for 1 h before they were exposed to Ang II (100 nM) for 12 h. n = 5, **P < 0.01.

Mentions: To study the potential interaction of HIF-1α with ACE, we inhibited HIF-1α by siRNA and ACE with captopril. Protein expression was analyzed by western blot. Transfection of MSCs with HIF-1α siRNA resulted in a significant decrease of ACE mRNA and protein expression (P < 0.05, Figure 3(a); P < 0.05, Figure 3(b)). Interestingly, a downregulation of HIF-1α protein expression was also observed when MSCs were pretreated with the ACE inhibitor, captopril (P < 0.01, Figure 3(c)). These results suggest that ACE and HIF-1α might interact with each other during their upregulation after MSCs are stimulated by Ang II.


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)

Interaction of HIF-1α with ACE in MSCs. (a) Real-time qPCR analysis of ACE mRNA level. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 12 h. n = 5, *P < 0.05. (b) Western blot analysis of ACE expression. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 6 h. n = 5, *P < 0.05. (c) Western blot analysis of HIF-1α. MSCs were pretreated with or without captopril (1 μM) for 1 h before they were exposed to Ang II (100 nM) for 12 h. n = 5, **P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Interaction of HIF-1α with ACE in MSCs. (a) Real-time qPCR analysis of ACE mRNA level. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 12 h. n = 5, *P < 0.05. (b) Western blot analysis of ACE expression. MSCs were pretreated by HIF-1α siRNA before being exposed to Ang II (100 nM) for 6 h. n = 5, *P < 0.05. (c) Western blot analysis of HIF-1α. MSCs were pretreated with or without captopril (1 μM) for 1 h before they were exposed to Ang II (100 nM) for 12 h. n = 5, **P < 0.01.
Mentions: To study the potential interaction of HIF-1α with ACE, we inhibited HIF-1α by siRNA and ACE with captopril. Protein expression was analyzed by western blot. Transfection of MSCs with HIF-1α siRNA resulted in a significant decrease of ACE mRNA and protein expression (P < 0.05, Figure 3(a); P < 0.05, Figure 3(b)). Interestingly, a downregulation of HIF-1α protein expression was also observed when MSCs were pretreated with the ACE inhibitor, captopril (P < 0.01, Figure 3(c)). These results suggest that ACE and HIF-1α might interact with each other during their upregulation after MSCs are stimulated by Ang II.

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