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

Arndt, Mary Ann; Battaglia, Valentina; Parisi, Eva; Lortie, Mark; Isome, Masato; Baskerville, Christopher; Pizzo, Donald; Ientile, Riccardo; Colombatto, Sebastiano; Toninello, Antonio; Satriano, Joseph

doi:10.1152/ajpcell.00529.2008

Cited by 65 publications

(51 citation statements)

References 76 publications

(91 reference statements)

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“…The secondary validation phase confirmed associations between the top-ranked loci; candidate genes, the topranked gene enrichment set, and the most significantly associated pathway are implicated in b-cell apoptosis (Tables 5 and 6, Supplemental Table 5). [47][48][49][50][51][52][53][54][55][56][57][58] b-Cell dysfunction may be the primary pathologic process in NODAT 18,20,21 and is discussed further in view of the genetic associations identified. Insulin resistance may also contribute to NODAT pathogenesis but this has not been conclusively proven.…”

Section: Discussionmentioning

confidence: 99%

“…53 Agmatine, a protein encoded by AGMAT (rs11580170), acts as a ROS scavenger to protect the mitochondrial membrane. 48 In animal models, agmatine also enhances insulin secretion. 49 Damaged mitochondria release cytochrome C and induce apoptosis via the activation of caspase 9 77 ; rs2020902 is located in the CASP9 gene.…”

Section: Discussionmentioning

confidence: 99%

“…49 Sustained demands on the endoplasmic reticulum (ER) during hyperglycemia result in cytoplasmic accumulation of calcium, 86,87 causing activation of the caspase cascade 86 and 57 regulates hepatic gluconeogenesis in mice 58 Where there is more than one candidate, the gene in closest proximity to the SNP was chosen (underlined). 48 In b cells, ER stress upregulates heat shock protein 40 expression; this correlates with increased apoptosis. 47 The transcription product of the DNAJC16 (rs7533125) gene forms part of the heat shock protein 40 complex.…”

Section: Discussionmentioning

confidence: 99%

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Genetics of New-Onset Diabetes after Transplantation

McCaughan

McKnight²,

Maxwell

2014

Journal of the American Society of Nephrology

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New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic b-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in b-cell apoptosis. These results corroborate recent clinical evidence implicating b-cell dysfunction in the pathophysiology of newonset diabetes after transplantation and support the pursuit of therapeutic strategies to protect b cells in the post-transplant period. One-year graft survival after renal transplantation is now excellent, exceeding 93% for organs donated after brain death and 96% for those from living donors. 1-3 Technical advancements in surgery, improved understanding of immunology, and innovative developments in pharmacology have altered the landscape of renal transplantation. The goal of preventing early graft loss has largely been achieved and arguably the greatest challenge now is the avoidance of late graft failure. Although there has been a considerable improvement in 1-year renal transplant survival, the rate of graft attrition after the first year remains frustratingly constant. 2,4 New-onset diabetes after transplantation (NODAT) is a common and serious disorder that curtails recipient survival. [5][6][7] NODAT is associated with cardiovascular complications [8][9][10][11] and develops in 2%-50% 12 of renal transplant recipients. Approximately 50% of recipients with NODAT require insulin therapy. [6][7][8][13][14][15] A number of clinical variables have been associated with NODAT, including black ethnicity, older recipient age, female sex, obesity, immunosuppression, and viral infections. 5,6,8,13,16,17 Until recently, the pathophysiology of NODAT was considered to be analogous to type 2 diabetes mellitus. Renal transplant recipients have increased insulin resistance compared with transplant-naïve persons with normal renal function. 18 In a nondiabetic renal transplant population, the m...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genetics of New-Onset Diabetes after Transplantation

McCaughan

McKnight²,

Maxwell

2014

Journal of the American Society of Nephrology

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“…Most of the experiments were performed on liver (Toninello et al 1985(Toninello et al , 1988a(Toninello et al , b, 1991(Toninello et al , 1992aSiliprandi et al 1988;Salvi et al 2006;Grillo et al 2007;Agostinelli et al 2010a;Martinis et al 2012), but this mechanism was also demonstrated in the heart ), brain (Tassani et al 1995;Battaglia et al 2010Battaglia et al , 2012, and kidney (Arndt et al 2009). The polyamine transporter is specific for the natural polyamines; agmatine has a different specific transporter, since all other amines or amino acids do not utilize these systems.…”

Section: Spermine Transport In the Matrixmentioning

confidence: 99%

Bidirectional fluxes of spermine across the mitochondrial membrane

et al. 2013

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The polyamine spermine is transported into the mitochondrial matrix by an electrophoretic mechanism having as driving force the negative electrical membrane potential (DW). The presence of phosphate increases spermine uptake by reducing DpH and enhancing DW. The transport system is a specific uniporter constituted by a protein channel exhibiting two asymmetric energy barriers with the spermine binding site located in the energy well between the two barriers. Although spermine transport is electrophoretic in origin, its accumulation does not follow the Nernst equation for the presence of an efflux pathway. Spermine efflux may be induced by different agents, such as FCCP, antimycin A and mersalyl, able to completely or partially reduce the DW value and, consequently, suppress or weaken the force necessary to maintain spermine in the matrix. However this efflux may also take place in normal conditions when the electrophoretic accumulation of the polycationic polyamine induces a sufficient drop in DW able to trigger the efflux pathway. The release of the polyamine is most probably electroneutral in origin and can take place in exchange with protons or in symport with phosphate anion. The activity of both the uptake and efflux pathways induces a continuous cycling of spermine across the mitochondrial membrane, the rate of which may be prominent in imposing the concentrations of spermine in the inner and outer compartment. Thus, this event has a significant role on mitochondrial permeability transition modulation and consequently on the triggering of intrinsic apoptosis.

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“…However, whether or not an increase of β-oxidation in the liver may link agmatine with increased HDL levels requires further investigation. Niacin, a model compound raising the blood level of HDL, is also known to increase β-oxidation of fatty acids in the liver [13,33,34]. In addition to the aforementioned effect on the expression of enzymes involved in mitochondrial fatty acids metabolism, agmatine has reduced the expression of the gene encoding of the enzyme involved in β-oxidation in the peroxisomes-Acaa1a (acetyl-Coenzyme A acyltransferase 1A).…”

Section: The Effect Of Agmatine On Mrna Expression Of Factors Involvementioning

confidence: 99%

Anti-atherosclerotic action of agmatine in apoE-knockout mice

Gębska

Niepsuj

Totoń‐Żurańska

et al. 2012

Vascular Pharmacology

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Abstract:Atherosclerosis is an inflammatory disease in which dysfunction of mitochondria play an important role, and disorders of lipid management intensify this process. Agmatine, an endogenous polyamine formed by decarboxylation of arginine, exerts a protective effect on mitochondria and modulates fatty acid metabolism. We investigated the effect of exogenous agmatine on the development of atherosclerosis and changes in lipid profile in apolipoprotein E knockout (apoE-/-) mice. Agmatine caused an approximate 40% decrease of atherosclerotic lesions, as estimated by en face and cross-section methods with an influence on macrophage but not on smooth muscle content in the plaques. Agmatine treatment did not changed gelatinase activity within the plaque area. What is more, the action of agmatine was associated with an increase in the number of high density lipoproteins (HDL) in blood. Real-Time PCR analysis showed that agmatine modulates liver mRNA levels of many factors involved in oxidation of fatty acid and cholesterol biosynthesis. Two-dimensional electrophoresis coupled with mass spectrometry identified 27 differentially expressed mitochondrial proteins upon agmatine treatment in the liver of apoE-/-mice, mostly proteins related to metabolism and apoptosis. In conclusion, prolonged administration of agmatine inhibits atherosclerosis in apoE-/-mice; however, the exact mechanisms linking observed changes and elevations of HDL plasma require further investigation.

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

Abstract: Pizzo DP, Ientile R, Colombatto S, Toninello A, Satriano J. The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis.

Cited by 65 publications

References 76 publications

Genetics of New-Onset Diabetes after Transplantation

Genetics of New-Onset Diabetes after Transplantation

Bidirectional fluxes of spermine across the mitochondrial membrane

Anti-atherosclerotic action of agmatine in apoE-knockout mice

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