Oh Young Jun, Pau Vanessa C, Steppan Jochen, Sikka Gautam, Bead Valeriani R, Nyhan Daniel, Levine Benjamin D, Berkowitz Dan E, Santhanam Lakshmi
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.
Amino Acids. 2017 Mar;49(3):695-704. doi: 10.1007/s00726-016-2295-z. Epub 2016 Jul 20.
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.
衰老与心肌细胞丢失增加、左心室肥厚以及细胞外基质的积累有关，这会导致心脏功能下降。基质交联酶组织转谷氨酰胺酶（TG2）在与年龄相关的心肌僵硬度和收缩功能中的作用仍未完全明确。在本研究中，我们研究了TG2在心脏功能中的作用，并确定TG2抑制是否能预防与年龄相关的心脏功能变化。通过渗透微型泵给18月龄雄性Fisher大鼠（研究组）注射转谷氨酰胺酶抑制剂胱胺或生理盐水（年龄匹配的对照组），持续12周。通过超声心动图和有创压力-容积环测定心脏功能。取出大鼠心脏，测定TG2的表达、活性和S-亚硝基化。以6月龄雄性大鼠作为对照。在生理盐水处理的衰老大鼠心脏中TG2活性显著增加，而在胱胺处理的心脏中未增加。TG2表达也随年龄增加，且不受胱胺处理的影响。与年轻大鼠相比，老年大鼠左心室（LV）收缩末期内径增加，缩短分数降低，胱胺对此无影响。然而，胱胺处理可维持LV充盈压的前负荷无关指数，并使舒张末期压力、舒张末期压力-容积关系和动脉弹性恢复至年轻水平。TG2活性增加导致与年龄相关的舒张期僵硬度增加，从而导致与年龄相关的舒张功能障碍。因此，TG2可能是与年龄相关的舒张性心力衰竭的一个新靶点。
