Canagliflozin protects against hyperglycemia-induced cerebrovascular injury by preventing blood-brain barrier (BBB) disruption via AMPK/Sp1/adenosine A2A receptor
Copyright © 2024 Elsevier B.V. All rights reserved..
Diabetes mellitus causes brain microvascular endothelial cell (MEC) damage, inducing dysfunctional angiogenic response and disruption of the blood-brain barrier (BBB). Canagliflozin is a revolutionary hypoglycemic drug that exerts neurologic and/or vascular-protective effects beyond glycemic control; however, its underlying mechanism remains unclear. In the present study, we hypothesize that canagliflozin ameliorates BBB permeability by preventing diabetes-induced brain MEC damage. Mice with high-fat diet/streptozotocin-induced diabetes received canagliflozin for 8 weeks. We assessed vascular integrity by measuring cerebrovascular neovascularization indices. The expression of specificity protein 1 (Sp1), as well as tight junction proteins (TJs), phosphorylated AMP-activated protein kinase (p-AMPK), and adenosine A2A receptors was examined. Mouse brain MECs were grown in high glucose (30 mM) to mimic diabetic conditions. They were treated with/without canagliflozin and assessed for migration and angiogenic ability. We also performed validation studies using AMPK activator (AICAR), inhibitor (Compound C), Sp1 small interfering RNA (siRNA), and adenosine A2A receptor siRNA. We observed that cerebral pathological neovascularization indices were significantly normalized in mice treated with canagliflozin. Increased Sp1 and adenosine A2A receptor expression and decreased p-AMPK and TJ expression were observed under diabetic conditions. Canagliflozin or AICAR treatment alleviated these changes. However, this alleviation effect of canagliflozin was diminished again after Compound C treatment. Either Sp1 siRNA or adenosine A2A receptor siRNA could increase the expression of TJs. Luciferase reporter assay confirmed that Sp1 could bind to the adenosine A2A receptor gene promoter. Our study identifies the AMPK/Sp1/adenosine A2A receptor pathway as a treatment target for diabetes-induced cerebrovascular injury.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:968 |
|---|---|
| Enthalten in: |
European journal of pharmacology - 968(2024) vom: 05. März, Seite 176381 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Zhiyi [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ejphar.2024.176381 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368305937 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368305937 | ||
| 003 | DE-627 | ||
| 005 | 20240311232257.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240211s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ejphar.2024.176381 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1323.xml |
| 035 | |a (DE-627)NLM368305937 | ||
| 035 | |a (NLM)38341077 | ||
| 035 | |a (PII)S0014-2999(24)00069-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Zhiyi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Canagliflozin protects against hyperglycemia-induced cerebrovascular injury by preventing blood-brain barrier (BBB) disruption via AMPK/Sp1/adenosine A2A receptor |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.03.2024 | ||
| 500 | |a Date Revised 11.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier B.V. All rights reserved. | ||
| 520 | |a Diabetes mellitus causes brain microvascular endothelial cell (MEC) damage, inducing dysfunctional angiogenic response and disruption of the blood-brain barrier (BBB). Canagliflozin is a revolutionary hypoglycemic drug that exerts neurologic and/or vascular-protective effects beyond glycemic control; however, its underlying mechanism remains unclear. In the present study, we hypothesize that canagliflozin ameliorates BBB permeability by preventing diabetes-induced brain MEC damage. Mice with high-fat diet/streptozotocin-induced diabetes received canagliflozin for 8 weeks. We assessed vascular integrity by measuring cerebrovascular neovascularization indices. The expression of specificity protein 1 (Sp1), as well as tight junction proteins (TJs), phosphorylated AMP-activated protein kinase (p-AMPK), and adenosine A2A receptors was examined. Mouse brain MECs were grown in high glucose (30 mM) to mimic diabetic conditions. They were treated with/without canagliflozin and assessed for migration and angiogenic ability. We also performed validation studies using AMPK activator (AICAR), inhibitor (Compound C), Sp1 small interfering RNA (siRNA), and adenosine A2A receptor siRNA. We observed that cerebral pathological neovascularization indices were significantly normalized in mice treated with canagliflozin. Increased Sp1 and adenosine A2A receptor expression and decreased p-AMPK and TJ expression were observed under diabetic conditions. Canagliflozin or AICAR treatment alleviated these changes. However, this alleviation effect of canagliflozin was diminished again after Compound C treatment. Either Sp1 siRNA or adenosine A2A receptor siRNA could increase the expression of TJs. Luciferase reporter assay confirmed that Sp1 could bind to the adenosine A2A receptor gene promoter. Our study identifies the AMPK/Sp1/adenosine A2A receptor pathway as a treatment target for diabetes-induced cerebrovascular injury | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AMP-Activated protein kinase | |
| 650 | 4 | |a Angiogenesis | |
| 650 | 4 | |a Blood-brain barrier | |
| 650 | 4 | |a Canagliflozin | |
| 650 | 4 | |a Diabetes | |
| 650 | 4 | |a Sp1 | |
| 650 | 7 | |a Receptor, Adenosine A2A |2 NLM | |
| 650 | 7 | |a Canagliflozin |2 NLM | |
| 650 | 7 | |a 0SAC974Z85 |2 NLM | |
| 650 | 7 | |a AMP-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.31 |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 700 | 1 | |a Hua, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Sinan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yueying |e verfasserin |4 aut | |
| 700 | 1 | |a Pang, Yuxin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Benshuai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Yuejia |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Jiping |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t European journal of pharmacology |d 1967 |g 968(2024) vom: 05. März, Seite 176381 |w (DE-627)NLM000029769 |x 1879-0712 |7 nnns |
| 773 | 1 | 8 | |g volume:968 |g year:2024 |g day:05 |g month:03 |g pages:176381 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ejphar.2024.176381 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 968 |j 2024 |b 05 |c 03 |h 176381 | ||