Aldosterone stimulation mediates cardiac metabolism remodeling via Sirt1/AMPK signaling in canine model

Naunyn Schmiedebergs Arch Pharmacol. 2019 Jul;392(7):851-863. doi: 10.1007/s00210-019-01641-2. Epub 2019 Mar 9.

Abstract

Aldosterone (Aldo), a pivotal hormone that is ubiquitously expressed in systemic tissues of mammals, is a crucial factor in the pathogenesis of cardiac disease. Accumulating evidence suggests that disturbances in cell energy metabolism are involved in increasing aldosterone levels. However, the precise mechanism underlying the impact of cardiac metabolic remodeling underlying aldosterone stimulation remains limited. In this work, we evaluated the underlying effect of aldosterone on regulating cardiac metabolism remodeling in a canine model. Fifteen beagle dogs were divided into a control group (n = 5), Aldo group (n = 5), and a group treated with spironolactone (SP), a mineralocorticoid receptor antagonist (n = 5), for 4 weeks. Blood pressure, electrocardiogram and respiratory parameters, H&E, Masson staining, ultrastructural changes, the adenosine triphosphate (ATP) and free fatty acid (FFA) levels of ventricular tissues, the level of mRNA, and the protein expression of key metabolic factors and regulators were assessed. The Sirt1/AMPK signaling pathway was significantly inhibited in the canine model of aldosterone stimulation, resulting in a reduction of the key downstream metabolic factors involved in glucose and fatty acid oxidation. The dysregulation of expression of key factors in glycogen metabolism led to glycogen deposition, an increase in FFA levels, a reduction in ATP levels, apoptosis, inflammatory cell infiltration, and mitochondrial damage in the ventricular myocardium. These effects were significantly restored by spironolactone. Aldosterone stimulation induced cardiac metabolic remodeling in ventricular cardiomyocytes possibly through the Sirt1/AMPK signaling pathway, implying that this pathway may provide a novel therapeutic target for cardiac metabolic remodeling.

Keywords: Aldosterone stimulation; Metabolic remodeling; Sirt1/AMPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aldosterone / administration & dosage
  • Aldosterone / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Dogs
  • Electrocardiography
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism*
  • Heart Ventricles / pathology
  • Male
  • Mineralocorticoid Receptor Antagonists / pharmacology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Signal Transduction
  • Sirtuin 1 / metabolism*
  • Spironolactone / pharmacology*
  • Ventricular Remodeling / drug effects*

Substances

  • Mineralocorticoid Receptor Antagonists
  • Spironolactone
  • Aldosterone
  • AMP-Activated Protein Kinases
  • Sirtuin 1