TY - JOUR
T1 - Role of tissue transglutaminase in age-associated ventricular stiffness
AU - Oh, Young Jun
AU - Pau, Vanessa C.
AU - Steppan, Jochen
AU - Sikka, Gautam
AU - Bead, Valeriani R.
AU - Nyhan, Daniel
AU - Levine, Benjamin D.
AU - Berkowitz, Dan E.
AU - Santhanam, Lakshmi
N1 - Funding Information:
This work was funded by an American Heart Association Beginning Grant-in-Aid 09BGIA2220181 (to LS) and National Heart, Lung, and Blood Institute grants R01HL105296 (to DEB) and R01AG017479 (to BDL).
Publisher Copyright:
© 2016, Springer-Verlag Wien.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - Cardiac aging
KW - Hypertrophy
KW - Tissue transglutaminase
UR - http://www.scopus.com/inward/record.url?scp=84979220824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979220824&partnerID=8YFLogxK
U2 - 10.1007/s00726-016-2295-z
DO - 10.1007/s00726-016-2295-z
M3 - Article
C2 - 27438265
AN - SCOPUS:84979220824
SN - 0939-4451
VL - 49
SP - 695
EP - 704
JO - Amino Acids
JF - Amino Acids
IS - 3
ER -