Reversal of Aortic Enlargement Induced by Increased Biomechanical Forces Requires AT1R Inhibition in Conjunction With AT2R Activation
Objective- Pharmacological inhibition of the AT1R (angiotensin II type 1 receptor) with losartan can attenuate ascending aortic remodeling induced by transverse aortic constriction (TAC). In this study, we investigated the role of the AT2R (angiotensin II type 2 receptor) and MasR (Mas receptor) in TAC-induced ascending aortic dilation and remodeling. Approach and Results- Wild-type C57BL/6J mice were subjected to sham or TAC surgeries in the presence and absence of various drugs. Aortic diameters were assessed by echocardiography, central blood pressure was measured in the ascending aorta 2 weeks post-operation, and histology and gene expression analyses completed. An angiotensin-converting enzyme inhibitor, captopril, decreased systolic blood pressure to the same level as losartan but did not attenuate aortic dilation, adventitial inflammation, medial collagen deposition, elastin breakage, or Mmp9 (matrix metalloproteinase-9) expression when compared with TAC mice. In contrast, co-administration of captopril with an AT2R agonist, compound 21, attenuated aortic dilation, medial collagen content, elastin breaks, and Mmp9 expression, whereas co-administration of captopril with a MasR agonist (AVE0991) did not reverse aortic dilation and led to aberrant aortic remodeling. An AT2R antagonist, PD123319, reversed the protective effects of losartan in TAC mice. Treatment with compound 21 alone showed no effect on TAC-induced aortic enlargement, blood pressure, elastin breakage, or Mmp9 expression. Conclusions- Our data indicate that when AT1R signaling is blocked, AT2R activation is a key modulator to prevent aortic dilation that occurs with TAC. These data suggest that angiotensin-converting enzyme inhibitor may not be as effective as losartan for slowing aneurysm growth because losartan requires intact AT2R signaling to prevent aortic enlargement.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
|---|---|
| Enthalten in: |
Arteriosclerosis, thrombosis, and vascular biology - 39(2019), 3 vom: 01. März, Seite 459-466 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhou, Zhen [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 13.01.2020 Date Revised 14.02.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1161/ATVBAHA.118.312158 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM292310374 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM292310374 | ||
| 003 | DE-627 | ||
| 005 | 20240214232041.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/ATVBAHA.118.312158 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1292.xml |
| 035 | |a (DE-627)NLM292310374 | ||
| 035 | |a (NLM)30602301 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhou, Zhen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Reversal of Aortic Enlargement Induced by Increased Biomechanical Forces Requires AT1R Inhibition in Conjunction With AT2R Activation |
| 264 | 1 | |c 2019 | |
| 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 13.01.2020 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Objective- Pharmacological inhibition of the AT1R (angiotensin II type 1 receptor) with losartan can attenuate ascending aortic remodeling induced by transverse aortic constriction (TAC). In this study, we investigated the role of the AT2R (angiotensin II type 2 receptor) and MasR (Mas receptor) in TAC-induced ascending aortic dilation and remodeling. Approach and Results- Wild-type C57BL/6J mice were subjected to sham or TAC surgeries in the presence and absence of various drugs. Aortic diameters were assessed by echocardiography, central blood pressure was measured in the ascending aorta 2 weeks post-operation, and histology and gene expression analyses completed. An angiotensin-converting enzyme inhibitor, captopril, decreased systolic blood pressure to the same level as losartan but did not attenuate aortic dilation, adventitial inflammation, medial collagen deposition, elastin breakage, or Mmp9 (matrix metalloproteinase-9) expression when compared with TAC mice. In contrast, co-administration of captopril with an AT2R agonist, compound 21, attenuated aortic dilation, medial collagen content, elastin breaks, and Mmp9 expression, whereas co-administration of captopril with a MasR agonist (AVE0991) did not reverse aortic dilation and led to aberrant aortic remodeling. An AT2R antagonist, PD123319, reversed the protective effects of losartan in TAC mice. Treatment with compound 21 alone showed no effect on TAC-induced aortic enlargement, blood pressure, elastin breakage, or Mmp9 expression. Conclusions- Our data indicate that when AT1R signaling is blocked, AT2R activation is a key modulator to prevent aortic dilation that occurs with TAC. These data suggest that angiotensin-converting enzyme inhibitor may not be as effective as losartan for slowing aneurysm growth because losartan requires intact AT2R signaling to prevent aortic enlargement | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a angiotensin II receptors | |
| 650 | 4 | |a ascending aortic remodeling | |
| 650 | 4 | |a biomechanical stress | |
| 650 | 4 | |a transverse aortic constriction | |
| 650 | 7 | |a AVE 0991 |2 NLM | |
| 650 | 7 | |a Angiotensin II Type 1 Receptor Blockers |2 NLM | |
| 650 | 7 | |a Angiotensin II Type 2 Receptor Blockers |2 NLM | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Mas |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Receptor, Angiotensin, Type 1 |2 NLM | |
| 650 | 7 | |a Receptor, Angiotensin, Type 2 |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 650 | 7 | |a PD 123319 |2 NLM | |
| 650 | 7 | |a 130663-39-7 |2 NLM | |
| 650 | 7 | |a Captopril |2 NLM | |
| 650 | 7 | |a 9G64RSX1XD |2 NLM | |
| 650 | 7 | |a Losartan |2 NLM | |
| 650 | 7 | |a JMS50MPO89 |2 NLM | |
| 700 | 1 | |a Peters, Andrew M |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shanzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Janda, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jiyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Arthur, Erin |e verfasserin |4 aut | |
| 700 | 1 | |a Kwartler, Callie S |e verfasserin |4 aut | |
| 700 | 1 | |a Milewicz, Dianna M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Arteriosclerosis, thrombosis, and vascular biology |d 1995 |g 39(2019), 3 vom: 01. März, Seite 459-466 |w (DE-627)NLM074658522 |x 1524-4636 |7 nnns |
| 773 | 1 | 8 | |g volume:39 |g year:2019 |g number:3 |g day:01 |g month:03 |g pages:459-466 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/ATVBAHA.118.312158 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 39 |j 2019 |e 3 |b 01 |c 03 |h 459-466 | ||