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

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: The genetic suppression of TG2 delays the age-induced endothelial dysfunction and histological modifications.

Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans

“…45 Transglutaminase 2 activity is inhibited by the vasoprotective molecule nitric oxide, 46 and we have previously shown that exposure to TMAO reduces vascular nitric oxide bioavailability by stimulating ROS production. 13 Furthermore, genetic knockdown 47 or pharmacological inhibition 48 of transglutaminase 2 lowers BP and improves vascular endothelium-dependent dilation in old rodents, and, although the evidence is mixed, 47 may attenuate age-related increases in aortic stiffness. 49 Thus, although we were unable to assess transglutaminase activity due to limited availability of aortic lysate, this remains a potential mechanism of interest moving forward.…”

Probing tissue transglutaminase mediated vascular smooth muscle cell aging using a novel transamidation-deficient Tgm2-C277S mouse model

“…The central role of TG2’s transamidation function in this diverse set of disease processes has resulted in a keen interest to develop selective and specific inhibitors that can be deployed in vivo to interrupt its transamidation reaction [ 17 – 19 ]. In the vasculature, TG2 inhibition or depletion protects against age-associated vascular stiffening [ 2 , 4 , 20 ] and delays resistance vessel remodeling induced by hypertensive and vasoconstrictive stimuli [ 21 – 23 ]. Thus, TG2’s transamidation function has an established role in vascular remodeling and stiffening.…”

Increased Transglutaminase 2 Expression and Activity in Rodent Models of Obesity/Metabolic Syndrome and Aging

“…Aging-associated fibrosis also occurs in other organs, including lungs ( Schafer et al, 2017 ; Sicard et al, 2018 ); the prevalence of chronic lung diseases and idiopathic pulmonary fibrosis in the elderly may reflect this occurrence ( Budinger et al, 2017 ). It has been previously reported that TG2 mediates cardiac ventricular ( Oh et al, 2017 ) and systemic arterial ( Armstrong et al, 2018 ) stiffness in rodent models of aging. Similar to that of the obesity/metabolic syndrome, it has been proposed that the aging process may be under the regulation of enhanced glycolysis with reduced mitochondrial function ( James et al, 2015 ; Feng et al, 2016 ; Cho et al, 2017 ; Jang et al, 2018 ).…”