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

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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.
Original languageEnglish
JournalClinical Science
Issue number24
Pages (from-to)2499–2516
Number of pages18
Publication statusPublished - 2019

Bibliographical 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 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.

ID: 231894699