Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function.

Abstract

BACKGROUND:

AMP-activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPKα2 gene (AMPKα2-KO) mice.

METHODS AND RESULTS:

T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPKα2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3 months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3 M). The rest continued normal diet or HFD until terminating study at the sixth month (6 M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3 M and 6 M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPKα2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3β pathway. However, these improving effects of SFN were abolished in AMPKα2-KO diabetic mice.

CONCLUSIONS:

AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3β signaling pathways.

• Authors: Yike Sun, Shanshan Zhou, Hua Guo, Jian Zhang, Tianjiao Ma, Yang Zheng, Zhiguo Zhang, Lu Cai
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 102 Pg. 154002 (01 2020) ISSN: 1532-8600 [Electronic] United States
• PMID: 31706979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cardiotonic Agents
• Isothiocyanates
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Sulfoxides
• Streptozocin
• AMP-Activated Protein Kinases
• sulforaphane

Topics

• AMP-Activated Protein Kinases (genetics, physiology)
• Animals
• Cardiotonic Agents (pharmacology, therapeutic use)
• Diabetes Mellitus, Experimental (chemically induced, complications, drug therapy)
• Diabetes Mellitus, Type 2 (chemically induced, complications, drug therapy)
• Diabetic Cardiomyopathies (genetics, pathology, prevention & control)
• Isothiocyanates (pharmacology, therapeutic use)
• Lipid Metabolism (drug effects, genetics)
• Lipidoses (genetics, metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2 (genetics, physiology)
• Signal Transduction (drug effects, genetics)
• Streptozocin
• Sulfoxides