miR-132-3p and KLF7 as novel regulators of aortic stiffening-associated EndMT in type 2 diabetes mellitus

Diabetology & Metabolic Syndrome

Research

Fang Cheng Wong¹  Sandip K. Rath²  Melanie S. Hulshoff³  Sabine Maamari⁴  Elisabeth M. Zeisberg⁴  Uwe Raaz⁴  Xingbo Xu⁴  Jolien Fledderus⁵  Guido Krenning⁵  Josephina Haunschild⁶  Isabel N. Schellinger⁷ 

[1] Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany;Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany;German Center for Cardiovascular Research (DZHK), Partner Site, Göttingen, Germany;Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany;German Center for Cardiovascular Research (DZHK), Partner Site, Göttingen, Germany;Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands;Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany;German Center for Cardiovascular Research (DZHK), Partner Site, Göttingen, Germany;University Heart Center, Göttingen, Germany;Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands;University Department for Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany;University Heart Center, Göttingen, Germany;Department of Endocrinology, Nephrology and Rheumatology, University of Leipzig Medical Center, Leipzig, Germany;

关键词: Aortic stiffness;    Endothelial-to-mesenchymal transition;    KLF7;    miR-132-3p;    Type 2 diabetes;   

DOI  :  10.1186/s13098-022-00966-y

 received in 2022-11-23, accepted in 2022-12-09,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe prevalence of diabetes mellitus has risen considerably and currently affects more than 422 million people worldwide. Cardiovascular diseases including myocardial infarction and heart failure represent the major cause of death in type 2 diabetes (T2D). Diabetes patients exhibit accelerated aortic stiffening which is an independent predictor of cardiovascular disease and mortality. We recently showed that aortic stiffness precedes hypertension in a mouse model of diabetes (db/db mice), making aortic stiffness an early contributor to cardiovascular disease development. Elucidating how aortic stiffening develops is a pressing need in order to halt the pathophysiological process at an early time point.MethodsTo assess EndMT occurrence, we performed co-immunofluorescence staining of an endothelial marker (CD31) with mesenchymal markers (α-SMA/S100A4) in aortic sections from db/db mice. Moreover, we performed qRT-PCR to analyze mRNA expression of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. To identify the underlying mechanism by which EndMT contributes to aortic stiffening, we used aortas from db/db mice and diabetic patients in combination with high glucose-treated human umbilical vein endothelial cells (HUVECs) as an in vitro model of diabetes-associated EndMT.ResultsWe demonstrate robust CD31/α-SMA and CD31/S100A4 co-localization in aortic sections of db/db mice which was almost absent in control mice. Moreover, we demonstrate a significant upregulation of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. As underlying regulator, we identified miR-132-3p as the most significantly downregulated miR in the micronome of db/db mice and high glucose-treated HUVECs. Indeed, miR-132-3p was also significantly downregulated in aortic tissue from diabetic patients. We identified Kruppel-like factor 7 (KLF7) as a target of miR-132-3p and show a significant upregulation of KLF7 in aortic sections of db/db mice and diabetic patients as well as in high glucose-treated HUVECs. We further demonstrate that miR-132-3p overexpression and KLF7 downregulation ameliorates EndMT in high glucose-treated HUVECs.ConclusionsWe demonstrate for the first time that EndMT contributes to aortic stiffening in T2D. We identified miR-132-3p and KLF7 as novel EndMT regulators in this context. Altogether, this gives us new insights in the development of aortic stiffening in T2D.

【 授权许可】

CC BY   
© The Author(s) 2023

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