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Role of tissue transglutaminase in age-associated ventricular stiffness

 Young Jun Oh  ;  Vanessa C. Pau  ;  Jochen Steppan  ;  Gautam Sikka  ;  Valeriani R. Bead  ;  Daniel Nyhan  ;  Benjamin D. Levine  ;  Dan E. Berkowitz  ;  Lakshmi Santhanam 
 AMINO ACIDS, Vol.49(3) : 695-704, 2017 
Journal Title
Issue Date
Aging/metabolism* ; Aging/pathology ; Animals ; Blood Pressure ; Cystamine/pharmacology ; Echocardiography ; Elasticity ; Enzyme Inhibitors/pharmacology ; Extracellular Matrix/drug effects ; Extracellular Matrix/enzymology ; Extracellular Matrix/pathology ; GTP-Binding Proteins/antagonists & inhibitors ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism* ; Gene Expression ; Heart Ventricles/enzymology* ; Heart Ventricles/physiopathology ; Hypertrophy, Left Ventricular/enzymology* ; Hypertrophy, Left Ventricular/genetics ; Hypertrophy, Left Ventricular/physiopathology ; Hypertrophy, Left Ventricular/prevention & control ; Infusion Pumps, Implantable ; Male ; Myocardium/enzymology ; Myocardium/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/enzymology* ; Myocytes, Cardiac/pathology ; Rats ; Rats, Inbred F344 ; Transglutaminases/antagonists & inhibitors ; Transglutaminases/genetics ; Transglutaminases/metabolism*
Cardiac aging ; Hypertrophy ; Tissue transglutaminase
Aging is associated with increased cardiomyocyte loss, left-ventricular hypertrophy, and the accumulation of extracellular matrix, which results in declining cardiac function. The role of the matrix crosslinking enzyme, tissue transglutaminase (TG2), in age-related myocardial stiffness, and contractile function remains incompletely understood. In this study, we examined the role of TG2 in cardiac function, and determined whether TG2 inhibition can prevent age-associated changes in cardiac function. Male Fisher rats (18-month-old) were administered the transglutaminase inhibitor cystamine (study group) or saline (age-matched controls) for 12 weeks via osmotic mini-pumps. Cardiac function was determined by echocardiography and invasive pressure-volume loops. Rat hearts were dissected out, and TG2 expression, activity, and S-nitrosation were determined. Young (6-month-old) males were used as controls. TG2 activity significantly increased in the saline-treated but not in the cystamine-treated aging rat hearts. TG2 expression also increased with age and was unaltered by cystamine treatment. Aged rats showed increased left ventricular (LV) end-systolic dimension and a decrease in fractional shortening compared with young, which was not affected by cystamine. However, cystamine treatment preserved the preload-independent index of LV filling pressure and restored end-diastolic pressure, end-diastolic pressure-volume relationships, and arterial elastance toward young. An increase in TG2 activity contributes to age-associated increase in diastolic stiffness, thereby contributing to age-associated diastolic dysfunction. TG2 may thus represent a novel target for age-associated diastolic heart failure.
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1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
Oh, Young Jun(오영준) ORCID logo https://orcid.org/0000-0002-6258-5695
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