Role of TLR4/MyD88/NF-κB signaling pathway in coronary microembolization-induced myocardial injury prevented and treated with nicorandil

Biomed Pharmacother. 2018 Oct:106:776-784. doi: 10.1016/j.biopha.2018.07.014. Epub 2018 Jul 11.

Abstract

Coronary microembolization (CME) is a common complication during the treatment of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). Nicorandil can be used to prevent myocardial injury after PCI to reduce the incidence of coronary no-reflow and slow flow, and play a role in myocardial protection, suggesting that its mechanism may be related to the inhibition of CME-induced inflammation of cardiomyocytes. However, the specific mechanism remains unclear. This study investigated the myocardial protective effects of nicorandil pretreatment on CME-induced myocardial injury and the specific mechanism of its inhibition of myocardial inflammation. An CME rat model exhibited CME-induced myocardial inflammation and the elevation of serum tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β based on echocardiography, myocardial enzyme detection, hematoxylin and eosin (HE) and hematoxylin-basic fuchsin-picric acid (HBFP) stainings, ELISA, quantitative real-time PCR, and western blotting. Nicorandil treatment seven days before CME induction effectively inhibited myocardial inflammation, ameliorated myocardial injury, and improved cardiac function, mainly by inhibiting Toll-like receptor 4 (TLR4)-mediated myeloid differentiation primary response protein 88 (MyD88)-dependent nuclear factor-kappa B (NF-κB) signaling. Rat neonatal cardiomyocyte experiments further confirmed that nicorandil ameliorated lipopolysaccharide (LPS)-induced myocardial inflammation and improved cardiomyocyte survival. The specific mechanisms mainly involved the inhibition of TLR4/MyD88/NF-κB signaling and the reduction of the inflammatory cytokines TNF-α and IL-1β released from cardiomyocytes. In summary, nicorandil significantly protected cardiomyocytes from CME-induced myocardial injury mainly by inhibiting TLR4/MyD88/NF-κB signaling, thereby reducing the onset of CME-induced myocardial inflammation. This could be one of the important mechanisms for reducing postoperative myocardial injury via PCI-preoperative prophylactic treatment with nicorandil.

Keywords: Coronary; Inflammation; Microembolization; Myocardial Injury; Nicorandil; TLR4/MyD88/NF-κB signaling pathway.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Survival
  • Coronary Stenosis / drug therapy*
  • Coronary Stenosis / etiology
  • Coronary Stenosis / metabolism
  • Coronary Stenosis / pathology
  • Cytoprotection
  • Disease Models, Animal
  • Embolism / drug therapy*
  • Embolism / etiology
  • Embolism / metabolism
  • Embolism / pathology
  • Inflammation Mediators / blood
  • Interleukin-1beta / blood
  • Lipopolysaccharides / pharmacology
  • Male
  • Microspheres
  • Myeloid Differentiation Factor 88 / metabolism*
  • Myocardial Infarction / etiology
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / prevention & control*
  • Myocarditis / etiology
  • Myocarditis / metabolism
  • Myocarditis / pathology
  • Myocarditis / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NF-kappa B / metabolism*
  • Nicorandil / pharmacology*
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Stroke Volume / drug effects
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / blood
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Function, Left / drug effects

Substances

  • Anti-Inflammatory Agents
  • IL1B protein, rat
  • Inflammation Mediators
  • Interleukin-1beta
  • Lipopolysaccharides
  • Myd88 protein, rat
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Nicorandil