title: Role of tissue transglutaminase in age-associated ventricular stiffness.
abstract: 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.
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.|Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Oh
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Pau
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sikka
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.
authors.forename: Valeriani R
authors.initials: VR
authors.lastname: Bead
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyhan
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Levine
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA. lsantha1@jhmi.edu.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001794:Blood Pressure; D003538:Cystamine / Q000494:pharmacology; D004452:Echocardiography; D004548:Elasticity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006352:Heart Ventricles / Q000201:enzymology* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D015918:Infusion Pumps, Implantable; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D011916:Rats, Inbred F344; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D003538:Cystamine
keywords: Cardiac aging; Hypertrophy; Tissue transglutaminase