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Weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice

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Abstract

The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress play in the progression of diabetes vascular complications are well recognized; however, the relative contribution and importance of these individual factors remain uncertain. At 6, 10, or 14 weeks old, blood samples and thoracic aortae were collected from db/db mice and their non-diabetic controls. Plasma samples were analyzed for glucose, 8-isoprostane, CRP, triglycerides, LDL, and HDL as markers of glycemic status, oxidative stress, inflammation, and dyslipidemia, respectively. The responses of the aortic rings to high KCl, phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside were examined. Statistical methods were used to estimate the strength of the association between plasma variables and vascular functions. Systemic inflammation occurred in db/db mice at an earlier age than did hyperglycemia or oxidative stress. Aortae of db/db showed augmented contractions to PE which were positively correlated with weight, plasma glucose, 8-isoprostane, and CRP. Also, db/db mice showed impaired endothelium-dependent ACh vasorelaxation which was negatively correlated with weight, plasma glucose, and 8-isoprostane. Multivariate analysis and stepwise modeling show that CRP is the major determinant of the contractile responses, while weight and HDL are the major determinants of ACh-induced relaxation. Among the traditional risk factors of obesity, hyperglycemia, oxidative stress, inflammation, and dyslipidemia, our study reveals that weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Our findings partially resolve the complexity of diabetes vasculopathies and suggest targeting weight loss and inflammation for effective therapeutic approaches.

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Abbreviations

ACh:

Acetylcholine

CRP:

C-reactive protein

HDL:

High-density lipoprotein

i.p.:

Intraperitoneal

KCl:

Potassium chloride

LDL:

Low-density lipoprotein

NO:

Nitric oxide

PE:

Phenylephrine

PSS:

Physiological salt solution

S.E.:

Standard error

SNP:

Sodium nitroprusside

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Acknowledgments

The study was supported by funds from the Canadian Heart and Stroke Foundation. Nada Sallam was gratefully funded by a scholarship from the Ministry of Higher Education, Egypt.

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The authors declare that they have no conflict of interest.

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  1. Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada, V6T1Z4

    Nada Sallam, Anat Fisher, Saeid Golbidi & Ismail Laher

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  1. Nada Sallam
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  2. Anat Fisher
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Correspondence to Ismail Laher.

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Sallam, N., Fisher, A., Golbidi, S. et al. Weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Naunyn-Schmiedeberg's Arch Pharmacol 383, 483–492 (2011). https://doi.org/10.1007/s00210-011-0614-1

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