Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs

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Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs. / Ludvigsen, Trine Pagh; Olsen, Lisbeth Høier; Pedersen, Henrik Duelund; Østergaard Christoffersen, Berit; Jensen, Lars Jørn.

In: Clinical Science, Vol. 133, No. 24, 2019, p. 2499–2516.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Ludvigsen, TP, Olsen, LH, Pedersen, HD, Østergaard Christoffersen, B & Jensen, LJ 2019, 'Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs', Clinical Science, vol. 133, no. 24, pp. 2499–2516. https://doi.org/10.1042/CS20191066

APA

Ludvigsen, T. P., Olsen, L. H., Pedersen, H. D., Østergaard Christoffersen, B., & Jensen, L. J. (2019). Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs. Clinical Science, 133(24), 2499–2516. https://doi.org/10.1042/CS20191066

Vancouver

Ludvigsen TP, Olsen LH, Pedersen HD, Østergaard Christoffersen B, Jensen LJ. Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs. Clinical Science. 2019;133(24):2499–2516. https://doi.org/10.1042/CS20191066

Author

Ludvigsen, Trine Pagh ; Olsen, Lisbeth Høier ; Pedersen, Henrik Duelund ; Østergaard Christoffersen, Berit ; Jensen, Lars Jørn. / Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs. In: Clinical Science. 2019 ; Vol. 133, No. 24. pp. 2499–2516.

Bibtex

@article{ed4b526e54724a9e8ad38b1e5c37940a,
title = "Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic G{\"o}ttingen Minipigs",
abstract = "Obesity and diabetes in humans are associated with hypertrophic remodeling and increased media:lumen ratio of small resistance arteries, which is an independent predictor of cardiovascular events. In order to minimize increases in media:lumen ratio, hypertrophic remodeling should be accompanied by outward remodeling. We aimed to investigate the mechanisms of structural remodeling in small pial arteries (PA) and terminal mesenteric arteries (TMA) from obese G{\"o}ttingen Minipigs with or without diabetes. G{\"o}ttingen Minipigs received either control diet (LC), high fat/high fructose/high cholesterol diet (FFC), or FFC diet with streptozotocin-induced diabetes (FFC/STZ) for 13 months. At study end (20 months), we assessed body weight, fasting plasma biochemistry, passive vessel dimensions, mRNA expression (MMP2, MMP9, TIMP1, TGM2, ROCK1, TGFBR2, and IGFR1 genes), and immunofluorescence in PAs and TMAs. We performed multiple linear correlation analyses using plasma values, structural data, and gene expression data. We detected outward hypertrophic remodeling in TMAs and hypertrophic remodeling in PAs from FFC/STZ animals. ROCK1 and TGM2 genes were up-regulated in PAs and TMAs from the FFC/STZ group. Passive lumen diameter of TMAs was correlated with plasma values of glucose, fructosamine, total cholesterol, and triglycerides. ROCK1 and TGM2 expressions in TMAs were correlated with passive lumen diameter, plasma glucose, fructosamine, and total cholesterol. ROCK1 and TGM2 proteins were immunolocalized in the media of PAs and TMAs, and their fluorescence levels were increased in the FFC/STZ group. Hyperglycemia/hyperlipidemia is involved in regulation of ROCK1 and TGM2 expression leading to outward remodeling of small resistance arteries in obese diabetic G{\"o}ttingen Minipigs.",
keywords = "Faculty of Health and Medical Sciences, G{\"o}ttingen minipigs, obesity, diabetes, Rho-kinase 1, Transglutaminase 2, remodeling, resistance arteries",
author = "Ludvigsen, {Trine Pagh} and Olsen, {Lisbeth H{\o}ier} and Pedersen, {Henrik Duelund} and {{\O}stergaard Christoffersen}, Berit and Jensen, {Lars J{\o}rn}",
note = "Clinical Perspectives: • Elevated risk of cardiovascular events in obese diabetic patients is predicted by hypertrophic remodeling and increased media:lumen-ratio of small arteries. We hypothesized that regulation of Rho-kinase 1 (ROCK1) and Transglutaminase 2 (TGM2) expression is involved in outward hypertrophic remodeling in small arteries from obese G{\"o}ttingen Minipigs with or without diabetes. • Obesity with diabetes was associated with increased expression of ROCK1 and TGM2 (mRNA and protein), outward hypertrophic remodeling in terminal mesenteric arteries, and hypertrophic remodeling in small pial arteries. The structural remodeling data correlated with fasting plasma glucose and lipid levels, and with ROCK1 and TGM2 expression. • In a translational minipig model with obesity and diabetes, hyperglycemia/hyperlipidemia and regulation of ROCK1 and TGM2 expression are involved in the control of outward remodeling and thereby arterial media:lumen-ratio. Obtaining more mechanistic insight into this regulation in humans could guide future drug development and potentially lead to lowering risk of cardiovascular events.",
year = "2019",
doi = "10.1042/CS20191066",
language = "English",
volume = "133",
pages = "2499–2516",
journal = "Clinical Science",
issn = "0143-5221",
publisher = "Portland Press Ltd.",
number = "24",

}

RIS

TY - JOUR

T1 - Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs

AU - Ludvigsen, Trine Pagh

AU - Olsen, Lisbeth Høier

AU - Pedersen, Henrik Duelund

AU - Østergaard Christoffersen, Berit

AU - Jensen, Lars Jørn

N1 - Clinical Perspectives: • Elevated risk of cardiovascular events in obese diabetic patients is predicted by hypertrophic remodeling and increased media:lumen-ratio of small arteries. We hypothesized that regulation of Rho-kinase 1 (ROCK1) and Transglutaminase 2 (TGM2) expression is involved in outward hypertrophic remodeling in small arteries from obese Göttingen Minipigs with or without diabetes. • Obesity with diabetes was associated with increased expression of ROCK1 and TGM2 (mRNA and protein), outward hypertrophic remodeling in terminal mesenteric arteries, and hypertrophic remodeling in small pial arteries. The structural remodeling data correlated with fasting plasma glucose and lipid levels, and with ROCK1 and TGM2 expression. • In a translational minipig model with obesity and diabetes, hyperglycemia/hyperlipidemia and regulation of ROCK1 and TGM2 expression are involved in the control of outward remodeling and thereby arterial media:lumen-ratio. Obtaining more mechanistic insight into this regulation in humans could guide future drug development and potentially lead to lowering risk of cardiovascular events.

PY - 2019

Y1 - 2019

N2 - Obesity and diabetes in humans are associated with hypertrophic remodeling and increased media:lumen ratio of small resistance arteries, which is an independent predictor of cardiovascular events. In order to minimize increases in media:lumen ratio, hypertrophic remodeling should be accompanied by outward remodeling. We aimed to investigate the mechanisms of structural remodeling in small pial arteries (PA) and terminal mesenteric arteries (TMA) from obese Göttingen Minipigs with or without diabetes. Göttingen Minipigs received either control diet (LC), high fat/high fructose/high cholesterol diet (FFC), or FFC diet with streptozotocin-induced diabetes (FFC/STZ) for 13 months. At study end (20 months), we assessed body weight, fasting plasma biochemistry, passive vessel dimensions, mRNA expression (MMP2, MMP9, TIMP1, TGM2, ROCK1, TGFBR2, and IGFR1 genes), and immunofluorescence in PAs and TMAs. We performed multiple linear correlation analyses using plasma values, structural data, and gene expression data. We detected outward hypertrophic remodeling in TMAs and hypertrophic remodeling in PAs from FFC/STZ animals. ROCK1 and TGM2 genes were up-regulated in PAs and TMAs from the FFC/STZ group. Passive lumen diameter of TMAs was correlated with plasma values of glucose, fructosamine, total cholesterol, and triglycerides. ROCK1 and TGM2 expressions in TMAs were correlated with passive lumen diameter, plasma glucose, fructosamine, and total cholesterol. ROCK1 and TGM2 proteins were immunolocalized in the media of PAs and TMAs, and their fluorescence levels were increased in the FFC/STZ group. Hyperglycemia/hyperlipidemia is involved in regulation of ROCK1 and TGM2 expression leading to outward remodeling of small resistance arteries in obese diabetic Göttingen Minipigs.

AB - Obesity and diabetes in humans are associated with hypertrophic remodeling and increased media:lumen ratio of small resistance arteries, which is an independent predictor of cardiovascular events. In order to minimize increases in media:lumen ratio, hypertrophic remodeling should be accompanied by outward remodeling. We aimed to investigate the mechanisms of structural remodeling in small pial arteries (PA) and terminal mesenteric arteries (TMA) from obese Göttingen Minipigs with or without diabetes. Göttingen Minipigs received either control diet (LC), high fat/high fructose/high cholesterol diet (FFC), or FFC diet with streptozotocin-induced diabetes (FFC/STZ) for 13 months. At study end (20 months), we assessed body weight, fasting plasma biochemistry, passive vessel dimensions, mRNA expression (MMP2, MMP9, TIMP1, TGM2, ROCK1, TGFBR2, and IGFR1 genes), and immunofluorescence in PAs and TMAs. We performed multiple linear correlation analyses using plasma values, structural data, and gene expression data. We detected outward hypertrophic remodeling in TMAs and hypertrophic remodeling in PAs from FFC/STZ animals. ROCK1 and TGM2 genes were up-regulated in PAs and TMAs from the FFC/STZ group. Passive lumen diameter of TMAs was correlated with plasma values of glucose, fructosamine, total cholesterol, and triglycerides. ROCK1 and TGM2 expressions in TMAs were correlated with passive lumen diameter, plasma glucose, fructosamine, and total cholesterol. ROCK1 and TGM2 proteins were immunolocalized in the media of PAs and TMAs, and their fluorescence levels were increased in the FFC/STZ group. Hyperglycemia/hyperlipidemia is involved in regulation of ROCK1 and TGM2 expression leading to outward remodeling of small resistance arteries in obese diabetic Göttingen Minipigs.

KW - Faculty of Health and Medical Sciences

KW - Göttingen minipigs

KW - obesity

KW - diabetes

KW - Rho-kinase 1

KW - Transglutaminase 2

KW - remodeling

KW - resistance arteries

U2 - 10.1042/CS20191066

DO - 10.1042/CS20191066

M3 - Journal article

C2 - 31830262

VL - 133

SP - 2499

EP - 2516

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 24

ER -

ID: 231894699