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Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress.
Toxicol Lett. 2018 Mar 01; 284:10-20.TL

Abstract

Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques. Diabetes compromised cardiac contractile function shown as reduced fractional shortening and ejection fraction, enlarged left ventricular end systolic/diastolic diameters, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged shortening and relengthening duration as well as impaired intracellular Ca2+ homeostasis, the effects of which were alleviated or reversed by aminoguanidine treatment. Diabetes also inhibited autophagy, increased ER stress and phosphorylation of pro-hypertrophic signaling molecules Akt and mTOR, the effect of which was reversed by aminoguanidine. In vitro study revealed that methylglyoxal-derived AGE (MG-AGE) incubation in isolated cardiomyocytes promoted oxidation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and production of superoxide, the effects of which were negated by the autophagy inducer rapamycin, the ER stress chaperone TUDCA or the antioxidant N-acetylcysteine. Taken together, these data revealed that inhibition of AGE formation rescues against experimental diabetes-induced cardiac remodeling and contractile dysfunction possible through regulation of autophagy and ER stress.

Authors+Show Affiliations

The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang, Jiangxi 330009, China.The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang, Jiangxi 330009, China.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 210032, China. Electronic address: jren@uwyo.edu.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 210032, China. Electronic address: zhang.yingmei@zs-hospital.sh.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29174818

Citation

Pei, Zhaohui, et al. "Inhibition of Advanced Glycation Endproduct (AGE) Rescues Against Streptozotocin-induced Diabetic Cardiomyopathy: Role of Autophagy and ER Stress." Toxicology Letters, vol. 284, 2018, pp. 10-20.
Pei Z, Deng Q, Babcock SA, et al. Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress. Toxicol Lett. 2018;284:10-20.
Pei, Z., Deng, Q., Babcock, S. A., He, E. Y., Ren, J., & Zhang, Y. (2018). Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress. Toxicology Letters, 284, 10-20. https://doi.org/10.1016/j.toxlet.2017.11.018
Pei Z, et al. Inhibition of Advanced Glycation Endproduct (AGE) Rescues Against Streptozotocin-induced Diabetic Cardiomyopathy: Role of Autophagy and ER Stress. Toxicol Lett. 2018 Mar 1;284:10-20. PubMed PMID: 29174818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress. AU - Pei,Zhaohui, AU - Deng,Qinqin, AU - Babcock,Sara A, AU - He,Emily Y, AU - Ren,Jun, AU - Zhang,Yingmei, Y1 - 2017/11/22/ PY - 2017/03/16/received PY - 2017/10/30/revised PY - 2017/11/21/accepted PY - 2017/11/28/pubmed PY - 2018/2/22/medline PY - 2017/11/28/entrez KW - Advanced glycation endproduct (AGE) KW - Autophagy KW - Cardiac KW - Diabetes KW - ER stress SP - 10 EP - 20 JF - Toxicology letters JO - Toxicol Lett VL - 284 N2 - Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques. Diabetes compromised cardiac contractile function shown as reduced fractional shortening and ejection fraction, enlarged left ventricular end systolic/diastolic diameters, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged shortening and relengthening duration as well as impaired intracellular Ca2+ homeostasis, the effects of which were alleviated or reversed by aminoguanidine treatment. Diabetes also inhibited autophagy, increased ER stress and phosphorylation of pro-hypertrophic signaling molecules Akt and mTOR, the effect of which was reversed by aminoguanidine. In vitro study revealed that methylglyoxal-derived AGE (MG-AGE) incubation in isolated cardiomyocytes promoted oxidation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and production of superoxide, the effects of which were negated by the autophagy inducer rapamycin, the ER stress chaperone TUDCA or the antioxidant N-acetylcysteine. Taken together, these data revealed that inhibition of AGE formation rescues against experimental diabetes-induced cardiac remodeling and contractile dysfunction possible through regulation of autophagy and ER stress. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/29174818/Inhibition_of_advanced_glycation_endproduct__AGE__rescues_against_streptozotocin_induced_diabetic_cardiomyopathy:_Role_of_autophagy_and_ER_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(17)31477-7 DB - PRIME DP - Unbound Medicine ER -