TY - JOUR
T1 - Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction
AU - Sciarretta, Sebastiano
AU - Yee, Derek
AU - Nagarajan, Narayani
AU - Bianchi, Franca
AU - Saito, Toshiro
AU - Valenti, Valentina
AU - Tong, Mingming
AU - Del Re, Dominic P.
AU - Vecchione, Carmine
AU - Schirone, Leonardo
AU - Forte, Maurizio
AU - Rubattu, Speranza
AU - Shirakabe, Akihiro
AU - Boppana, V. Subbarao
AU - Volpe, Massimo
AU - Frati, Giacomo
AU - Zhai, Peiyong
AU - Sadoshima, Junichi
N1 - Publisher Copyright:
© 2018 American College of Cardiology Foundation
PY - 2018/5/8
Y1 - 2018/5/8
N2 - Background: Trehalose (TRE) is a natural, nonreducing disaccharide synthesized by lower organisms. TRE exhibits an extraordinary ability to protect cells against different kinds of stresses through activation of autophagy. However, the effect of TRE on the heart during stress has never been tested. Objectives: This study evaluated the effects of TRE administration in a mouse model of chronic ischemic remodeling. Methods: Wild-type (WT) or beclin 1+/− mice were subjected to permanent ligation of the left anterior descending artery (LAD) and then treated with either placebo or trehalose (1 mg/g/day intraperitoneally for 48 h, then 2% in the drinking water). After 4 weeks, echocardiographic, hemodynamic, gravimetric, histological, and biochemical analyses were conducted. Results: TRE reduced left ventricular (LV) dilation and increased ventricular function in mice with LAD ligation compared with placebo. Sucrose, another nonreducing disaccharide, did not exert protective effects during post-infarction LV remodeling. Trehalose administration to mice overexpressing GFP-tagged LC3 significantly increased the number of GFP-LC3 dots, both in the presence and absence of chloroquine administration. TRE also increased cardiac LC3-II levels after 4 weeks following myocardial infarction (MI), indicating that it induced autophagy in the heart in vivo. To evaluate whether TRE exerted beneficial effects through activation of autophagy, trehalose was administered to beclin 1+/− mice. The improvement of LV function, lung congestion, cardiac remodeling, apoptosis, and fibrosis following TRE treatment observed in WT mice were all significantly blunted in beclin 1+/− mice. Conclusions: TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.
AB - Background: Trehalose (TRE) is a natural, nonreducing disaccharide synthesized by lower organisms. TRE exhibits an extraordinary ability to protect cells against different kinds of stresses through activation of autophagy. However, the effect of TRE on the heart during stress has never been tested. Objectives: This study evaluated the effects of TRE administration in a mouse model of chronic ischemic remodeling. Methods: Wild-type (WT) or beclin 1+/− mice were subjected to permanent ligation of the left anterior descending artery (LAD) and then treated with either placebo or trehalose (1 mg/g/day intraperitoneally for 48 h, then 2% in the drinking water). After 4 weeks, echocardiographic, hemodynamic, gravimetric, histological, and biochemical analyses were conducted. Results: TRE reduced left ventricular (LV) dilation and increased ventricular function in mice with LAD ligation compared with placebo. Sucrose, another nonreducing disaccharide, did not exert protective effects during post-infarction LV remodeling. Trehalose administration to mice overexpressing GFP-tagged LC3 significantly increased the number of GFP-LC3 dots, both in the presence and absence of chloroquine administration. TRE also increased cardiac LC3-II levels after 4 weeks following myocardial infarction (MI), indicating that it induced autophagy in the heart in vivo. To evaluate whether TRE exerted beneficial effects through activation of autophagy, trehalose was administered to beclin 1+/− mice. The improvement of LV function, lung congestion, cardiac remodeling, apoptosis, and fibrosis following TRE treatment observed in WT mice were all significantly blunted in beclin 1+/− mice. Conclusions: TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.
KW - autophagy
KW - cardiac remodeling
KW - heart failure
KW - trehalose
KW - ventricular function
UR - http://www.scopus.com/inward/record.url?scp=85046540313&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2018.02.066
DO - 10.1016/j.jacc.2018.02.066
M3 - Article
C2 - 29724354
AN - SCOPUS:85046540313
SN - 0735-1097
VL - 71
SP - 1999
EP - 2010
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 18
ER -