TLR4 knockout attenuated high fat diet-induced cardiac dysfunction via NF-κB/JNK-dependent activation of autophagy

Biochim Biophys Acta Mol Basis Dis. 2017 Aug;1863(8):2001-2011. doi: 10.1016/j.bbadis.2017.01.010. Epub 2017 Jan 17.

Abstract

Obesity is commonly associated with a low grade systemic inflammation, which may contribute to the onset and development of myocardial remodeling and contractile dysfunction. Toll-like receptor 4 (TLR4) plays an important role in innate immunity and inflammation although its role in high fat diet-induced obesity cardiac dysfunction remains elusive. This study was designed to examine the effect of TLR4 ablation on high fat diet intake-induced cardiac anomalies, if any, and underlying mechanism(s) involved. Wild-type (WT) and TLR4 knockout mice were fed normal or high fat (60% calorie from fat) diet for 12weeks prior to assessment of mechanical and intracellular Ca2+ properties. The inflammatory signaling proteins (TLR4, NF-κB, and JNK) and autophagic markers (Atg5, Atg12, LC3B and p62) were evaluated. Our results revealed that high fat diet intake promoted obesity, marked decrease in fractional shortening, and cardiomyocyte contractile capacity with dampened intracellular Ca2+ release and clearance, elevated ROS generation and oxidative stress as measured by aconitase activity, the effects of which were significantly attenuated by TLR4 knockout. In addition, high fat intake downregulated levels of Atg5, Atg12 and LC3B, while increasing p62 accumulation. TLR4 knockout itself did not affect Atg5, Atg12, LC3B and p62 levels while it reconciled high fat diet intake-induced changes in autophagy. In addition, TLR4 knockout alleviated high fat diet-induced phosphorylation of IKKβ, JNK and mTOR. In vitro study revealed that palmitic acid suppressed cardiomyocyte contractile function, the effect of which was inhibited the TLR4 inhibitor CLI-095, the JNK inhibitor AS601245 or the NF-κB inhibitor Celastrol. Taken together, these data showed that TLR4 knockout ameliorated high fat diet-induced cardiac contractile and intracellular Ca2+ anomalies through inhibition of inflammation and ROS, possibly through a NF-κB/JNK-dependent activation of autophagy. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.

Keywords: Autophagy; Contractile function; Heart; High fat diet; TLR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetonitriles / pharmacology
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Benzothiazoles / pharmacology
  • Calcium Signaling / drug effects*
  • Calcium Signaling / genetics
  • Dietary Fats / adverse effects*
  • Dietary Fats / pharmacology
  • Heart Diseases* / chemically induced
  • Heart Diseases* / genetics
  • Heart Diseases* / metabolism
  • Heart Diseases* / pathology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Pentacyclic Triterpenes
  • Reactive Oxygen Species / metabolism
  • Sulfonamides / pharmacology
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / deficiency*
  • Triterpenes / pharmacology

Substances

  • 1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile
  • Acetonitriles
  • Apoptosis Regulatory Proteins
  • Benzothiazoles
  • Dietary Fats
  • NF-kappa B
  • Pentacyclic Triterpenes
  • Reactive Oxygen Species
  • Sulfonamides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Triterpenes
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • MAP Kinase Kinase 4
  • celastrol