The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

Am J Physiol Cell Physiol. 2009 Jun;296(6):C1411-9. doi: 10.1152/ajpcell.00529.2008. Epub 2009 Mar 25.

Abstract

Agmatine, an endogenous metabolite of arginine, selectively suppresses growth in cells with high proliferative kinetics, such as transformed cells, through depletion of intracellular polyamine levels. In the present study, we depleted intracellular polyamine content with agmatine to determine if attrition by cell death contributes to the growth-suppressive effects. We did not observe an increase in necrosis, DNA fragmentation, or chromatin condensation in Ha-Ras-transformed NIH-3T3 cells administered agmatine. In response to Ca(2+)-induced oxidative stress in kidney mitochondrial preparations, agmatine demonstrated attributes of a free radical scavenger by protecting against the oxidation of sulfhydryl groups and decreasing hydrogen peroxide content. The functional outcome was a protective effect against Ca(2+)-induced mitochondrial swelling and mitochondrial membrane potential collapse. We also observed decreased expression of proapoptotic Bcl-2 family members and of execution caspase-3, implying antiapoptotic potential. Indeed, we found that apoptosis induced by camptothecin or 5-fluorourocil was attenuated in cells administered agmatine. Agmatine may offer an alternative to the ornithine decarboxylase inhibitor difluoromethyl ornithine for depletion of intracellular polyamine content while avoiding the complications of increasing polyamine import and reducing the intracellular free radical scavenger capacity of polyamines. Depletion of intracellular polyamine content with agmatine suppressed cell growth, yet its antioxidant capacity afforded protection from mitochondrial insult and resistance to cellular apoptosis. These results could explain the beneficial outcomes observed with agmatine in models of injury and disease.

Publication types

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

MeSH terms

  • Agmatine / metabolism*
  • Animals
  • Antioxidants / metabolism*
  • Apoptosis* / drug effects
  • Arginine / metabolism*
  • Calcium / metabolism
  • Camptothecin / toxicity
  • Caspase 3 / metabolism
  • Cell Proliferation
  • Cytoprotection
  • DNA Fragmentation
  • Fluorouracil / toxicity
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Swelling
  • NIH 3T3 Cells
  • Polyamines / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats

Substances

  • Antioxidants
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Polyamines
  • Proto-Oncogene Proteins c-bcl-2
  • Agmatine
  • Arginine
  • Casp3 protein, mouse
  • Caspase 3
  • Calcium
  • Fluorouracil
  • Camptothecin