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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/C1411    most recent 00529.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Arndt, M. A. Articles by Satriano, J. PubMed PubMed Citation Articles by Arndt, M. A. Articles by Satriano, J.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

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

¹Division of Nephrology-Hypertension, ²The Stein Institute for Research on Aging, Department of Medicine, and ³Department of Neurosciences, University of California-San Diego, and ⁴Veterans Administration, San Diego Healthcare System, La Jolla, California; ⁵Department of Biochemistry, University of Padova, Padova, Italy; ⁶Division of Nephrology, Hospital University Arnau de Vilanova, Lleida, Spain; ⁷Department of Pediatrics, School of Medicine, Fukushima Medical University, Fukushima, Japan; ⁸Department Biochemical, Physiological and Nutritional Sciences, University of Messina, Messina; and ⁹Department of Medicine and Experimental Oncology, University of Torino, Torino, Italy

Submitted 14 October 2008 ; accepted in final form 23 March 2009

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 Ca²⁺-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 Ca²⁺-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.

oxidative stress; polyamines; free radical scavenger; Bcl-2; caspase-3