Abstract
Rationale: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Methods and Results: Acta2 -/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2 -/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2 -/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. Conclusions: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1903-1915 |
| Number of pages | 13 |
| Journal | Circulation Research |
| Volume | 120 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 9 2017 |
Fingerprint
Keywords
- angiotensins
- aorta
- losartan
- mutation
- reactive oxygen species
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement. / Chen, Jiyuan; Peters, Andrew; Papke, Christina L.; Villamizar, Carlos; Ringuette, Lea Jeanne; Cao, Jiumei; Wang, Shanzhi; Ma, Shuangtao; Gong, Limin; Byanova, Katerina L.; Xiong, Jian; Zhu, Michael X.; Madonna, Rosalinda; Kee, Patrick; Geng, Yong Jian; Brasier, Allan R.; Davis, Elaine C.; Prakash, Siddharth; Kwartler, Callie S.; Milewicz, Dianna M.
In: Circulation Research, Vol. 120, No. 12, 09.06.2017, p. 1903-1915.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement
AU - Chen, Jiyuan
AU - Peters, Andrew
AU - Papke, Christina L.
AU - Villamizar, Carlos
AU - Ringuette, Lea Jeanne
AU - Cao, Jiumei
AU - Wang, Shanzhi
AU - Ma, Shuangtao
AU - Gong, Limin
AU - Byanova, Katerina L.
AU - Xiong, Jian
AU - Zhu, Michael X.
AU - Madonna, Rosalinda
AU - Kee, Patrick
AU - Geng, Yong Jian
AU - Brasier, Allan R.
AU - Davis, Elaine C.
AU - Prakash, Siddharth
AU - Kwartler, Callie S.
AU - Milewicz, Dianna M.
PY - 2017/6/9
Y1 - 2017/6/9
N2 - Rationale: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Methods and Results: Acta2 -/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2 -/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2 -/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. Conclusions: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.
AB - Rationale: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Methods and Results: Acta2 -/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2 -/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2 -/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. Conclusions: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.
KW - angiotensins
KW - aorta
KW - losartan
KW - mutation
KW - reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85020660311&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020660311&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.117.310563
DO - 10.1161/CIRCRESAHA.117.310563
M3 - Article
VL - 120
SP - 1903
EP - 1915
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 12
ER -