Angiotensin-(1-9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway

Cell Death Differ. 2020 Sep;27(9):2586-2604. doi: 10.1038/s41418-020-0522-3. Epub 2020 Mar 9.

Abstract

Angiotensin-(1-9) is a peptide from the noncanonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. In the present study we aimed to elucidate it, basing us initially on previous work from our group and colleagues who proved a relationship between disturbances in mitochondrial morphology and calcium handling, associated with the setting of cardiac hypertrophy. Our first finding was that angiotensin-(1-9) can induce mitochondrial fusion through DRP1 phosphorylation. Secondly, angiotensin-(1-9) blocked mitochondrial fission and intracellular calcium dysregulation in a model of norepinephrine-induced cardiomyocyte hypertrophy, preventing the activation of the calcineurin/NFAT signaling pathway. To further investigate angiotensin-(1-9) anti-hypertrophic mechanism, we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1-9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that PKA activity is necessary for the effects of angiotensin-(1-9) over mitochondrial dynamics, calcium handling and its anti-hypertrophic effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / pharmacology*
  • Animals
  • Animals, Newborn
  • Calcium / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytosol / metabolism
  • Dynamins / metabolism
  • Hypertrophy
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / drug effects*
  • Models, Biological
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology*
  • Myocytes, Cardiac / ultrastructure
  • NFATC Transcription Factors / metabolism
  • Norepinephrine / pharmacology
  • Peptide Fragments / pharmacology*
  • Phosphorylation / drug effects
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Up-Regulation / drug effects

Substances

  • Intracellular Signaling Peptides and Proteins
  • MIRN129 microRNA, rat
  • MicroRNAs
  • NFATC Transcription Factors
  • Peptide Fragments
  • angiotensin I (1-9)
  • protein kinase modulator
  • Angiotensin I
  • Cyclic AMP-Dependent Protein Kinases
  • Dnm1l protein, rat
  • Dynamins
  • Calcium
  • Norepinephrine