Transglutaminase 2 (TG2) is an enzyme with multiple conformations. In its open conformation, TG2 exhibits transamidase activity linked to fibrosis, arterial remodeling, and endothelial dysfunction, a process enhanced by high glucose in endothelial cells. However, the closed conformation of TG2 contributes to transmembrane signaling and nitric oxide (NO)-dependent vasorelaxation. LDN 27219, a reversible allosteric inhibitor, stabilizes TG2 in its closed conformation. We examined whether pharmacological modulation of TG2 into its closed conformation induces vasorelaxation and enhances endothelium-dependent and independent relaxation in resistance arteries from age-matched diabetic (n = 14) and non-diabetic patients (n = 14) (age 71 (Standard Error of the Mean: ± 2)). Subcutaneous arteries (diameter 133–1013 µm) were isolated from abdominal fat biopsies. TG2 mRNA expression and transamidase activity were assessed via RT-qPCR and 5-biotin(amido)pentylamine (5-BP) incorporation, while vascular reactivity was measured using wire myography. TG2 mRNA was highly expressed without significant differences between the groups and LDN 27219 induced concentration-dependent vasorelaxation in arteries from both groups. Sex-specific analysis revealed that potentiation of acetylcholine-induced vasorelaxation by LDN 27219 was driven by increased TG2 expression in non-diabetic females, whereas no effect was observed in arteries from non-diabetic males. Among diabetic patients, LDN 27219 increased maximal acetylcholine-induced vasorelaxation in males only. LDN 27219 did not affect endothelium-independent relaxation to sodium nitroprusside in either group. In conclusion, TG2 is expressed in human resistance arteries, and LDN 27219 induced vasorelaxation, selectively enhancing ACh relaxation in non-diabetic females, likely owing to increased TG2 expression. This finding underscores the importance of sex differences in TG2 modulation of vasorelaxation.

01 Dec 2024·European Journal of Pharmacology

Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model

Article

Author: Buus, Niels Henrik ; Touyz, Rhian M ; Montezano, Augusto C ; Montezano, Augusto C. ; De Araujo, Isabela Bastos Binotti Abreu ; Nørregaard, Rikke ; Pinilla, Estéfano ; Simonsen, Ulf ; Juste, Nina ; Rios, Francisco J. ; Prat-Duran, Judit ; Touyz, Rhian M. ; Rios, Francisco J ; Binotti Abreu De Araujo, Isabela Bastos

BACKGROUNDTransglutaminase 2 (TG2) is a multifunctional enzyme involved in fibrosis by promoting transforming-growth-factor-β1 and crosslinking of extracellular matrix proteins. These functions are dependent on the open conformation, while the closed state of TG2 can induce vasodilation. We explored the putative protective role of TG2 in its closed state on development of renal fibrosis and blood pressure (BP) regulation.METHODSWe studied the unilateral ureteral obstruction (UUO) mouse model treated with LDN27219, which promotes the closed conformation of TG2. Mice were subjected to 7 days UUO or sham operation and treated with vehicle (n = 10), LDN27219 (15 mg/kg/12 h, n = 9) or candesartan (5 mg/kg/day, n = 10) as a clinically comparator. Renal expression of TG2 and pro-fibrotic mediators were evaluated by Western blotting, qPCR and histology, and BP by tail-cuff measurements.RESULTSObstructed kidneys showed increased mRNA and protein expression of fibronectin, collagen 3α1 (Col3α1), α-smooth muscle actin and collagen staining. Despite increased renal TG2 mRNA, protein expression was reduced in all UUO groups, but with increased transamidase activity in the vehicle and candesartan groups. LDN27219 reduced mRNA expression of fibronectin and Col3α1, but their protein expression remained unchanged. In contrast to LDN27219, candesartan lowered BP without affecting expression of pro-fibrotic biomarkers.CONCLUSIONRenal TG2 mRNA and protein expression levels seem dissociated, with transamidase activity being increased. LDN27219 influences kidney pro-fibrotic markers at the mRNA level and attenuates transamidase activity but without affecting collagen content or BP. Our findings suggest that TG2 in its closed conformation has anti-fibrotic effects at the molecular level.

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Indication	Highest Phase	Country/Location	Organization	Date
Neurodegenerative Diseases	Preclinical	US	Harvard University	01 Apr 2005

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