Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension

Sonu Kashyap, Gina Warner, Zeng Hu, Feng Gao, Mazen Osman, Yousif Al Saiegh, Karen R. Lien, Karl A Nath, Joseph Peter Grande

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kid-ney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10–14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.

Original languageEnglish (US)
Article numbere0187062
JournalPLoS One
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2017

Fingerprint

Renovascular Hypertension
Surgery
hypertension
Dissection
Phenotype
phenotype
mice
129 Strain Mouse
Tissue
Renal Artery Obstruction
Cardiovascular system
kidneys
Macrophages
Polytetrafluoroethylene
Matrix Metalloproteinases
arteries
Muscle Cells
Kidney
Fibrosis
Necrosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension. / Kashyap, Sonu; Warner, Gina; Hu, Zeng; Gao, Feng; Osman, Mazen; Al Saiegh, Yousif; Lien, Karen R.; Nath, Karl A; Grande, Joseph Peter.

In: PLoS One, Vol. 12, No. 10, e0187062, 01.10.2017.

Research output: Contribution to journalArticle

Kashyap, S, Warner, G, Hu, Z, Gao, F, Osman, M, Al Saiegh, Y, Lien, KR, Nath, KA & Grande, JP 2017, 'Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension', PLoS One, vol. 12, no. 10, e0187062. https://doi.org/10.1371/journal.pone.0187062
Kashyap S, Warner G, Hu Z, Gao F, Osman M, Al Saiegh Y et al. Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension. PLoS One. 2017 Oct 1;12(10). e0187062. https://doi.org/10.1371/journal.pone.0187062
Kashyap, Sonu ; Warner, Gina ; Hu, Zeng ; Gao, Feng ; Osman, Mazen ; Al Saiegh, Yousif ; Lien, Karen R. ; Nath, Karl A ; Grande, Joseph Peter. / Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension. In: PLoS One. 2017 ; Vol. 12, No. 10.
@article{6ac7e9788175405cb13b1945ed07f7ee,
title = "Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension",
abstract = "Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kid-ney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5{\%} for KO mice with RAS, 4.1{\%} for KO sham mice, 1.2{\%} for WT with RAS, and 1.8{\%} for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10–14 days following surgery in 62.5{\%} of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.",
author = "Sonu Kashyap and Gina Warner and Zeng Hu and Feng Gao and Mazen Osman and {Al Saiegh}, Yousif and Lien, {Karen R.} and Nath, {Karl A} and Grande, {Joseph Peter}",
year = "2017",
month = "10",
day = "1",
doi = "10.1371/journal.pone.0187062",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension

AU - Kashyap, Sonu

AU - Warner, Gina

AU - Hu, Zeng

AU - Gao, Feng

AU - Osman, Mazen

AU - Al Saiegh, Yousif

AU - Lien, Karen R.

AU - Nath, Karl A

AU - Grande, Joseph Peter

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kid-ney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10–14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.

AB - Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kid-ney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10–14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.

UR - http://www.scopus.com/inward/record.url?scp=85032448619&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032448619&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0187062

DO - 10.1371/journal.pone.0187062

M3 - Article

C2 - 29073282

AN - SCOPUS:85032448619

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e0187062

ER -