Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement

Jiyuan Chen, Andrew Peters, Christina L. Papke, Carlos Villamizar, Lea Jeanne Ringuette, Jiumei Cao, Shanzhi Wang, Shuangtao Ma, Limin Gong, Katerina L. Byanova, Jian Xiong, Michael X. Zhu, Rosalinda Madonna, Patrick Kee, Yong Jian Geng, Allan R. Brasier, Elaine C. Davis, Siddharth Prakash, Callie S. Kwartler, Dianna M. Milewicz

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1903-1915
Number of pages13
JournalCirculation Research
Volume120
Issue number12
DOIs
StatePublished - Jun 9 2017

Fingerprint

Cell Enlargement
Angiotensin II
Angiotensin Receptors
Smooth Muscle Myocytes
Smooth Muscle
Actins
Aorta
Actin Cytoskeleton
Reactive Oxygen Species
Angiotensin II Type 1 Receptor Blockers
Thoracic Aortic Aneurysm
Aortic Diseases
Losartan
Vascular Diseases
Vascular Smooth Muscle
Echocardiography
Dissection
Dilatation
Protein Isoforms
Kidney

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 journalArticle

Chen, J, Peters, A, Papke, CL, Villamizar, C, Ringuette, LJ, Cao, J, Wang, S, Ma, S, Gong, L, Byanova, KL, Xiong, J, Zhu, MX, Madonna, R, Kee, P, Geng, YJ, Brasier, AR, Davis, EC, Prakash, S, Kwartler, CS & Milewicz, DM 2017, 'Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement', Circulation Research, vol. 120, no. 12, pp. 1903-1915. https://doi.org/10.1161/CIRCRESAHA.117.310563
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. / Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement. In: Circulation Research. 2017 ; Vol. 120, No. 12. pp. 1903-1915.
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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.",
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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

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