Dataset Information

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer.

ABSTRACT:

Background

Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics-related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied.

Objectives

This study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab.

Methods

Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months after doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points.

Results

Age, hypertension, body mass index, and African-American race were independently associated with ≥1 of baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline and increases in ADMA were observed at 1 and 2 months (all p < 0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI]: 1.12 to 9.96) and 2.70 (95% CI: 1.35 to 5.41), respectively, and 0.78 (95% CI: 0.64 to 0.97) for arginine at 1 month.

Conclusions

In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

SUBMITTER: Finkelman BS

PROVIDER: S-EPMC5665653 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer.

Finkelman Brian S BS Putt Mary M Wang Teresa T Wang Le L Narayan Hari H Domchek Susan S DeMichele Angela A Fox Kevin K Matro Jennifer J Shah Payal P Clark Amy A Bradbury Angela A Narayan Vivek V Carver Joseph R JR Tang W H Wilson WHW Ky Bonnie B

Journal of the American College of Cardiology 20170701 2

<h4>Background</h4>Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics-related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied.<h4>Objectives</h4>This study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab.<h4>Me ...[more]

PMID: 28683962

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Project description:L-Arginine (L-Arg), the precursor of nitric oxide (NO), plays an important role in muscle function. Fast-twitch glycolytic fibres are more susceptible to age-related atrophy than slow-twitch oxidative fibres. The effect of L-Arg/NO on protein metabolism of fast- and slow-twitch muscle fibres was evaluated in chickens. In Exp. 1, 48 chicks at 1 day old were divided into 4 groups of 12 birds and subjected to 4 treatments: basal diet without supplementation or supplemented with 1% L-Arg, and water supplemented with or without L-nitro-arginine methyl ester (L-NAME, 18.5 mM). In Exp. 2, 48 chicks were divided into 4 groups of 12 birds fed with the basal diet and subjected to the following treatments: tap water (control), tap water supplemented with L-NAME (18.5 mM), or molsidomine (MS, 0.1 mM), or 18.5 mM L-NAME + 0.1 mM MS (NAMS). The regulatory effect of L-Arg/NO was further investigated in vitro with myoblasts obtained from chicken embryo pectoralis major (PM) and biceps femoris (BF). In vivo, dietary L-Arg supplementation increased breast (+14.94%, P < 0.05) and thigh muscle mass (+23.40%, P < 0.05); whereas, MS treatment had no detectable influence. However, L-NAME treatment blocked the beneficial influence of L-Arg on muscle development. L-Arg decreased (P < 0.05) protein synthesis rate, phosphorylated mTOR and ribosomal protein S6 kinase beta-1 (p70S6K) levels in breast muscle, which was recovered by L-NAME treatment. In vitro, L-Arg or sodium nitroprusside (SNP) reduced protein synthesis rate, suppressed phosphorylated mTOR/p70S6K and decreased atrogin-1 and muscle RING finger 1 (MuRF1) in myoblasts from PM muscle (P < 0.05). L-NAME abolished the inhibitory effect of L-Arg on protein synthesis and the mTOR/p70S6K pathway. However, myoblasts from BF muscle showed the weak influence. Moreover, blocking the mTOR/p70S6K pathway with rapamycin suppressed protein synthesis of the 2 types of myoblasts; whereas, the protein expression of atrogin-1 and MuRF1 levels were restricted only in myoblasts from PM muscle. In conclusion, L-Arg/NO/mTOR/p70S6K pathway enhances protein accumulation and muscle development in fast-twitch glycolytic muscle in chickens. L-Arg/NO regulates protein turnover in a muscle fibre specific way, which highlights the potential clinical application in fast-twitch glycolytic muscle fibres.

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Dataset Information

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer.

Background

Objectives

Methods

Results

Conclusions

Publications

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer.

Similar Datasets

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