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Treatment with brain natriuretic peptide prevents the development of cardiac dysfunction in obese diabetic db/db mice

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Abstract

Aims/hypothesis

Obesity and diabetes increase the risk of developing cardiovascular diseases and heart failure. These metabolic disorders are generally reflected by natriuretic peptide system deficiency. Since brain natriuretic peptide (BNP) is known to influence metabolism and cardioprotection, we investigated the effect of chronic exogenous BNP treatment on adverse myocardial consequences related to obesity and diabetes.

Methods

Ten-week-old C57BL/KsJ-db/db obese diabetic mice (db/db) and their lean control littermates (db/+) were treated with BNP (0.6 μg kg−1 h−1) or saline for 12 weeks (n = 10/group). Serial blood and tomography analysis were performed. Cardiac function was determined by echocardiography, and biochemical and histological heart and fat analyses were also performed.

Results

BNP treatment resulted in an average increase in plasma BNP levels of 70 pg/ml. An improvement in the metabolic profile of db/db mice was observed, including a reduction in fat content, increased insulin sensitivity, improved glucose tolerance and lower blood glucose, despite increased food intake. db/db mice receiving saline displayed both early systolic and diastolic dysfunction, whereas these functional changes were prevented by BNP treatment. The cardioprotective effects of BNP were attributed to the inhibition of cardiomyocyte apoptosis, myocardial fibrosis, cardiac hypertrophy and the AGE–receptor for AGE (RAGE) system as well as normalisation of cardiac AMP-activated protein kinase and endothelial nitric oxide synthase activities.

Conclusions/interpretation

Our results indicate that chronic BNP treatment at low dose improves the metabolic profile and prevents the development of myocardial dysfunction in db/db mice.

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Abbreviations

AMPK:

AMP-activated protein kinase

ANP:

Atrial natriuretic peptide

BAX:

BCL2-associated X

BCL:

B cell lymphoma

BNP:

Brain natriuretic peptide

CASP3:

Caspase-3

CVF:

Collagen volume fraction

ITT:

Insulin tolerance test

LV:

Left ventricle

eNOS:

Endothelial nitric oxide synthase

NP:

Natriuretic peptide

NPR:

Natriuretic peptide receptor

RAGE:

Receptor for AGE

UCP1:

Uncoupling protein-1

veh:

Vehicle

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Acknowledgements

We are very grateful to J.-L. Chiasson (Department of Medicine, Chief, Endocrinology Division, CHUM, University of Montreal, QC, Canada) for his valuable comments and criticism.

Funding

This study was supported by grants from the CIHR and Canadian Heart and Stroke Foundation (to JG, MJ) and the Diabetes Action Research and Education Foundation (to TLB). EP was supported by a fellowship grant from the CIHR and Canadian Heart and Stroke Foundation.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

EP had full access to all the data in the study and takes responsibility for the accuracy of the data analysis. JG and MJ are the principal investigators for the project. EP, AM and BAD acquired the data. EP, MJ, TLB and JG conceived and designed the study question. EP and AM analysed the data, and EP, MJ, TLB and JG interpreted the data. EP and MJ drafted the manuscript, and all authors critically revised the manuscript for important intellectual content and have approved the final version.

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Authors and Affiliations

  1. Cardiovascular Biochemistry Laboratory, CRCHUM (7-134), Tour Viger, 900 St-Denis St., Montreal, Quebec, H2X 0A9, Canada

    Eric Plante, Ahmed Menaouar, Bogdan A. Danalache, Marek Jankowski & Jolanta Gutkowska

  2. Department of Medicine, University of Montreal, Montreal, Quebec, Canada

    Eric Plante, Bogdan A. Danalache, Marek Jankowski & Jolanta Gutkowska

  3. Department of Physiology, Midwestern University, Glendale, AZ, USA

    Tom L. Broderick

Authors
  1. Eric Plante
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  2. Ahmed Menaouar
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  3. Bogdan A. Danalache
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  4. Tom L. Broderick
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  5. Marek Jankowski
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  6. Jolanta Gutkowska
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Corresponding author

Correspondence to Jolanta Gutkowska.

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Plante, E., Menaouar, A., Danalache, B.A. et al. Treatment with brain natriuretic peptide prevents the development of cardiac dysfunction in obese diabetic db/db mice. Diabetologia 57, 1257–1267 (2014). https://doi.org/10.1007/s00125-014-3201-4

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  • DOI: https://doi.org/10.1007/s00125-014-3201-4

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