Knockdown of transglutaminase-2 prevents early age-induced vascular changes in mice1.

Dinani Matoso Filho Armstrong,Karen Ruggeri Saad,Lakshmi Santhanam,Djalma José Fagundes,Anderson Da Costa Armstrong,Dan Ezra Berkowitz,Gautam Sikka,Murched Omar Taha,William Rodrigues De Freitas

doi:10.1590/s0102-865020180110000006

Abstract

To determine whether the absence of transglutaminase 2 enzyme (TG2) in TG2 knockout mice (TG2-/-) protect them against early age-related functional and histological arterial changes. Pulse wave velocity (PWV) was measured using non-invasive Doppler and mean arterial pressure (MAP) was measured in awake mice using tail-cuff system. Thoracic aortas were excised for evaluation of endothelial dependent vasodilation (EDV) by wire myography, as well as histological analyses. PWV and MAP were similar in TG2-/-mice to age-matched wild type (WT) control mice. Old WT mice exhibited a markedly attenuated EDV as compared to young WT animals. The TG2-/-young and old mice had enhanced EDV responses (p<0.01) as compared to WT mice. There was a significant increase in TG2 crosslinks by IHC in WT old group compared to Young, with no stain in the TG2-/-animals. Optical microscopy examination of Old WT mice aorta showed thinning and fragmentation of elastic laminae. Young WT mice, old and young TG2-/-mice presented regularly arranged and parallel elastic laminae of the tunica media. The genetic suppression of TG2 delays the age-induced endothelial dysfunction and histological modifications.

Highlights

Age is the most important predictor of cardiovascular disease, even in the absence of modifiable risk factors[1]
Endothelial nitric oxide-dependent aortic relaxation was increased in transglutaminase 2 enzyme (TG2) knockout mice
The endothelial dependent vasodilation (EDV) responses to acetylcholine in aged mice were significantly attenuated compared to those from the young animals

Summary

Introduction

Age is the most important predictor of cardiovascular disease, even in the absence of modifiable risk factors[1]. The arterial ageing process results from alterations in the properties of all elements of the vascular wall, including endothelium, vascular smooth muscle, and extra-cellular matrix (ECM)[2,3]. These alterations contribute to the development of vascular stiffness and to an additional impairment of the endothelial function, both considered as independent risk factors for cardiovascular morbidity and mortality[4,5,6]. TG2 expression has been involved in multiple vascular pathophysiological processes, including vascular remodeling[12,13,14], atherosclerosis[15], vascular calcification[16] and age-dependent aortic stiffening[8,17]

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Discussion

Conclusion