3,3′-Diindolylmethane Protects against Cardiac Hypertrophy via 5′-Adenosine Monophosphate-Activated Protein Kinase-α2

Jing Zong,Hong-Liang Li,Qing-Qing Wu,Qi-Zhu Tang,Heng Zhou,Jie-Yu Zhang,Hai-Peng Guo,Yan Zhang,Jia Dai,Zhou-Yan Bian,Rui Zhang,Yuan Yuan,Wei Deng,Xiongwen Chen

doi:10.1371/journal.pone.0053427

Abstract

Purpose3,3′-Diindolylmethane (DIM) is a natural component of cruciferous plants. It has strong antioxidant and anti-angiogenic effects and promotes the apoptosis of a variety of tumor cells. However, little is known about the critical role of DIM on cardiac hypertrophy. In the present study, we investigated the effects of DIM on cardiac hypertrophy.MethodsMultiple molecular techniques such as Western blot analysis, real-time PCR to determine RNA expression levels of hypertrophic, fibrotic and oxidative stress markers, and histological analysis including H&E for histopathology, PSR for collagen deposition, WGA for myocyte cross-sectional area, and immunohistochemical staining for protein expression were used.ResultsIn pre-treatment and reverse experiments, C57/BL6 mouse chow containing 0.05% DIM (dose 100 mg/kg/d DIM) was administered one week prior to surgery or one week after surgery, respectively, and continued for 8 weeks after surgery. In both experiments, DIM reduced to cardiac hypertrophy and fibrosis induced by aortic banding through the activation of 5′-adenosine monophosphate-activated protein kinase-α2 (AMPKα2) and inhibition of mammalian target of the rapamycin (mTOR) signaling pathway. Furthermore, DIM protected against cardiac oxidative stress by regulating expression of estrogen-related receptor-alpha (ERRα) and NRF2 etc. The cardioprotective effects of DIM were ablated in mice lacking functional AMPKα2.ConclusionDIM significantly improves left ventricular function via the activation of AMPKα2 in a murine model of cardiac hypertrophy.

Highlights

Cardiac hypertrophy is a chronic compensatory condition, in which the heart has suffered from long-term overload
DIM reduced to cardiac hypertrophy and fibrosis induced by aortic banding through the activation of 59-adenosine monophosphate-activated protein kinase-a2 (AMPKa2) and inhibition of mammalian target of the rapamycin signaling pathway
DIM Attenuated Cardiac Hypertrophy Induced by Pressure Overload in WT Mice. Both DIM-treated and vehicle-treated mice were submitted to Aortic banding (AB) or a sham surgery for 8 weeks to determine whether DIM antagonized and reversed the hypertrophic response to pressure overload

Summary

Introduction

Cardiac hypertrophy is a chronic compensatory condition, in which the heart has suffered from long-term overload. Cardiac hypertrophy can be divided into physiological hypertrophy and pathological hypertrophy [1]. Physiological hypertrophy is a reversible condition that is mainly found in the development of healthy people and pregnant or exercising person. Pathological hypertrophy is mainly characterized by the accumulation of various stimulatory signals (such as heart damage, neurohormonal factors, and aortic stenosis) and is a compensatory response. When the stimulatory factors are sustained, the compensatory mechanism becomes a decompensatory mechanism that eventually leads to heart failure [2,3]. There is no effective method to prevent and treat cardiac hypertrophy. Therapies for cardiac hypertrophy still focus on regulating hemodynamics. Pharmacological interventions targeting the molecular changes involved in cardiac hypertrophy may provide promising approaches for protecting against cardiac hypertrophy and progression to heart failure

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