Antihypertrophic Effects of Small Molecules that Maintain Mitochondrial ATP Levels Under Hypoxia

EBioMedicine. 2017 Oct:24:147-158. doi: 10.1016/j.ebiom.2017.09.022. Epub 2017 Sep 19.

Abstract

Since impaired mitochondrial ATP production in cardiomyocytes is thought to lead to heart failure, a drug that protects mitochondria and improves ATP production under disease conditions would be an attractive treatment option. In this study, we identified small-molecule drugs, including the anti-parasitic agent, ivermectin, that maintain mitochondrial ATP levels under hypoxia in cardiomyocytes. Mechanistically, transcriptomic analysis and gene silencing experiments revealed that ivermectin increased mitochondrial ATP production by inducing Cox6a2, a subunit of the mitochondrial respiratory chain. Furthermore, ivermectin inhibited the hypertrophic response of human induced pluripotent stem cell-derived cardiomyocytes. Pharmacological inhibition of importin β, one of the targets of ivermectin, exhibited protection against mitochondrial ATP decline and cardiomyocyte hypertrophy. These findings indicate that maintaining mitochondrial ATP under hypoxia may prevent hypertrophy and improve cardiac function, providing therapeutic options for mitochondrial dysfunction.

Keywords: Cardiomyocytes; Hypertrophy; Hypoxia; Mitochondrial ATP; Phenotypic screening.

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Cardiotonic Agents / pharmacology*
  • Cell Hypoxia / drug effects*
  • Cells, Cultured
  • Electron Transport Complex IV / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / drug effects
  • Ivermectin / pharmacology
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Small Molecule Libraries / pharmacology*
  • beta Karyopherins / metabolism

Substances

  • Cardiotonic Agents
  • Small Molecule Libraries
  • beta Karyopherins
  • Ivermectin
  • Adenosine Triphosphate
  • Electron Transport Complex IV