Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload

Journal of Molecular and Cellular Cardiology
Arti V ShindeNikolaos G Frangogiannis

Abstract

Tissue transglutaminase (tTG) is a multifunctional protein with a wide range of enzymatic and non-enzymatic functions. We have recently demonstrated that tTG expression is upregulated in the pressure-overloaded myocardium and exerts fibrogenic actions promoting diastolic dysfunction, while preventing chamber dilation. Our current investigation dissects the in vivo and in vitro roles of the enzymatic effects of tTG on fibrotic remodeling in pressure-overloaded myocardium. Using a mouse model of transverse aortic constriction, we demonstrated perivascular and interstitial tTG activation in the remodeling pressure-overloaded heart. tTG inhibition through administration of the selective small molecule tTG inhibitor ERW1041E attenuated left ventricular diastolic dysfunction and reduced cardiomyocyte hypertrophy and interstitial fibrosis in the pressure-overloaded heart, without affecting chamber dimensions and ejection fraction. In vivo, tTG inhibition markedly reduced myocardial collagen mRNA and protein levels and attenuated transcription of fibrosis-associated genes. In contrast, addition of exogenous recombinant tTG to fibroblast-populated collagen pads had no significant effects on collagen transcription, and instead increased ...Continue Reading

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Citations

Jun 21, 2019·Circulation Research·Nikolaos G Frangogiannis
Jan 10, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chinmayee D BhediKrishna C Penumatsa
Oct 13, 2020·Frontiers in Physiology·Krishna C PenumatsaBarry L Fanburg
Nov 3, 2020·Cardiovascular Research·Nikolaos G Frangogiannis
Dec 22, 2020·Cellular Signalling·Lily S Neff, Amy D Bradshaw
Jul 30, 2018·Molecular Aspects of Medicine·Nikolaos G Frangogiannis
Aug 8, 2021·Cells·Beatriz Delgado-ValeroErnesto Martínez-Martínez
Dec 11, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Francisco I Ramirez-PerezGuido Lastra

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