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.

Trehalose-induced activation of autophagy improves cardiac remodeling after myocardial infarction / Sciarretta, Sebastiano; Yee, Derek; Nagarajan, Narayani; Bianchi, Franca; Saito, Toshiro; Valenti, Valentina; Tong, Mingming; Del Re, Dominic P.; Vecchione, Carmine; Schirone, Leonardo; Forte, Maurizio; Rubattu, Speranza; Shirakabe, Akihiro; Boppana, V. Subbarao; Volpe, Massimo; Frati, Giacomo; Zhai, Peiyong; Sadoshima, Junichi. - In: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. - ISSN 0735-1097. - STAMPA. - 71:18(2018), pp. 1999-2010. [10.1016/j.jacc.2018.02.066]

Trehalose-induced activation of autophagy improves cardiac remodeling after myocardial infarction

Sciarretta, Sebastiano;Valenti, Valentina;Vecchione, Carmine;Schirone, Leonardo;Rubattu, Speranza;Volpe, Massimo;Frati, Giacomo;
2018

Abstract

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.
2018
autophagy; cardiac remodeling; heart failure; trehalose; ventricular function; cardiology and cardiovascular medicine
01 Pubblicazione su rivista::01a Articolo in rivista
Trehalose-induced activation of autophagy improves cardiac remodeling after myocardial infarction / Sciarretta, Sebastiano; Yee, Derek; Nagarajan, Narayani; Bianchi, Franca; Saito, Toshiro; Valenti, Valentina; Tong, Mingming; Del Re, Dominic P.; Vecchione, Carmine; Schirone, Leonardo; Forte, Maurizio; Rubattu, Speranza; Shirakabe, Akihiro; Boppana, V. Subbarao; Volpe, Massimo; Frati, Giacomo; Zhai, Peiyong; Sadoshima, Junichi. - In: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. - ISSN 0735-1097. - STAMPA. - 71:18(2018), pp. 1999-2010. [10.1016/j.jacc.2018.02.066]
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