Co-expression of glycosylated aquaporin-1 and transcription factor NFAT5 contributes to aortic stiffness in diabetic and atherosclerosis-prone mice.

Rosalinda Madonna,Raffaele De Caterina,Péter Ferdinandy,Nino Cocco,Yong‐Jian Geng,Vanessa Doria,Anikó Görbe,Sante Donato Pierdomenico

doi:10.1111/jcmm.14843

Abstract

Increased stiffness characterizes the early change in the arterial wall with subclinical atherosclerosis. Proteins inducing arterial stiffness in diabetes and hypercholesterolaemia are largely unknown. This study aimed at determining the pattern of protein expression in stiffening aorta of diabetic and hypercholesterolaemic mice. Male Ins2+/Akita mice were crossbred with ApoE−/− (Ins2+/Akita: ApoE−/−) mice. Relative aortic distension (relD) values were determined by ultrasound analysis and arterial stiffness modulators by immunoblotting. Compared with age‐ and sex‐matched C57/BL6 control mice, the aortas of Ins2+/Akita, ApoE−/− and Ins2+/Akita:ApoE−/− mice showed increased aortic stiffness. The aortas of Ins2+/Akita, ApoE−/− and Ins2+/Akita:ApoE−/− mice showed greater expression of VCAM‐1, collagen type III, NADPH oxidase and iNOS, as well as reduced elastin, with increased collagen type III‐to‐elastin ratio. The aorta of Ins2+/Akita and Ins2+/Akita:ApoE−/− mice showed higher expression of eNOS and cytoskeletal remodelling proteins, such as F‐actin and α‐smooth muscle actin, in addition to increased glycosylated aquaporin (AQP)‐1 and transcription factor NFAT5, which control the expression of genes activated by high glucose‐induced hyperosmotic stress. Diabetic and hypercholesterolaemic mice have increased aortic stiffness. The association of AQP1 and NFAT5 co‐expression with aortic stiffness in diabetes and hypercholesterolaemia may represent a novel molecular pathway or therapeutic target.

Highlights

Compared with non-diabetic individuals, diabetic patients suffer more aggressive, rapidly progressive atherosclerosis often with earlier complications, such as arterial stiffness.[1,2] This is because altered glucose metabolism in diabetes can modify and increase the impact of comorbidities, such as hypercholesterolaemia.[3]
From the six mammalian actin genes, the expression of vascular smooth muscle cells (VSMCs)-specific cytoskeleton actin ASMA appears to be regulated by both CArG promoter elements, such as the transcriptional coactivator myocardin,[13] and nuclear factor of activated T cells 5 (NFAT5).14 NFAT5, a rel/NF-κB family member, is a transcription factor activated by hyperosmolar stress, which regulates the expression of osmosensing genes, including those involved in cell migration and cytoskeletal remodelling.[12,15,16,17,18]
| 2863 characterized by increased arterial stiffness, in a manner associated with up-regulation of hypertonicity-responsive factors, such as AQ1 and NFAT5, along with genes implicated in early inflammation and atherosclerosis, such as vascular cell adhesion molecule (VCAM)-1; cytoskeletal remodelling, such as filamentous actin (F-actin) and ASMA; endothelial dysfunction, such as iNOS and eNOS; and reactive oxygen species (ROS) generation, such as NADPH oxidase

Summary

Introduction

Compared with non-diabetic individuals, diabetic patients suffer more aggressive, rapidly progressive atherosclerosis often with earlier complications, such as arterial stiffness.[1,2] This is because altered glucose metabolism in diabetes can modify and increase the impact of comorbidities, such as hypercholesterolaemia.[3]. Pathogenetic mechanisms and biomarkers of early-stage vascular abnormalities, such as arterial stiffening, can be identified through animal models of diabetes and hypercholesterolaemia.[10] Cytoskeletal reorganization and arterial remodelling are adaptive responses to altered biomechanical stress. From the six mammalian actin genes, the expression of VSMC-specific cytoskeleton actin ASMA appears to be regulated by both CArG promoter elements, such as the transcriptional coactivator myocardin,[13] and NFAT5.14 NFAT5, a rel/NF-κB family member, is a transcription factor activated by hyperosmolar stress, which regulates the expression of osmosensing genes, including those involved in cell migration and cytoskeletal remodelling.[12,15,16,17,18]

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