title: Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway.
abstract: Type 2 diabetes mellitus (T2DM)-induced cardiomyopathy is associated with cardiac oxidative stress, inflammation, and remodeling. Sulforaphane (SFN), an isothiocyanate naturally presenting in widely consumed vegetables, particularly broccoli, plays an important role in cardiac protection from diabetes. We investigated the effect of SFN on T2DM-induced cardiac lipid accumulation and subsequent cardiomyopathy. Male C57BL/6J mice were fed a high-fat diet for 3months to induce insulin resistance, followed by a treatment with 100mg/kg body-weight streptozotocin to induce hyperglycemia; we referred to it as the T2DM mouse model. Other age-matched mice were fed a normal diet as control. T2DM and control mice were treated with or without 4-month SFN at 0.5mg/kg daily five days a week. At the study's end, cardiac function was assessed. SFN treatment significantly attenuated cardiac remodeling and dysfunction induced by T2DM. SFN treatment also significantly inhibited cardiac lipid accumulation, measured by Oil Red O staining, and improved cardiac inflammation oxidative stress and fibrosis, shown by down-regulating diabetes-induced PAI-1, TNF-α, CTGF, TGF-β, 3-NT, and 4-HNE expression. Elevated 4-HNE resulted in the increase of 4-HNE-LKB1 adducts that should inhibit LKB1 and subsequent AMPK activity. SFN upregulated the expression of Nrf2 and its downstream genes, NQO1 and HO-1, decreased 4-HNE-LKB1 adducts and then reversed diabetes-induced inhibition of LKB1/AMPK and its downstream targets, including sirtuin 1, PGC-1α, phosphorylated acetyl-CoA carboxylase, carnitine palmitoyl transferase-1, ULK1, and light chain-3 II. These results suggest that SFN treatment to T2DM mice may attenuate the cardiac oxidative stress-induced inhibition of LKB1/AMPK signaling pathway, thereby preventing T2DM-induced lipotoxicity and cardiomyopathy.
authors.affiliation: Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China; Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China; Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China; Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China; Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mellen
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Maiying
authors.initials: M
authors.lastname: Kong
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; Department of Pathology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China.
authors.forename: Junlian
authors.initials: J
authors.lastname: Gu
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China. Electronic address: zhengyang@jlu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: l0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D058065:Diabetic Cardiomyopathies / Q000517:prevention & control*; D059305:Diet, High-Fat / Q000009:adverse effects; D017879:Isothiocyanates / Q000494:pharmacology / Q000627:therapeutic use*; D050356:Lipid Metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013454:Sulfoxides
chemical_list: D002316:Cardiotonic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; C016766:sulforaphane
keywords: Cardiac lipotoxicity; Cardiomyopathy; LKB1/AMPK pathway; Oxidative stress; Sulforaphane; Type 2 diabetes