Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome

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Abstract

Background

There is a preponderance of evidence implicating diabetes with increased coronary artery disease (CAD) and calcification (CAC) in human patients with metabolic syndrome (MetS), but the effect of diabetes on CAD severity in animal models remains controversial. We investigated whether diabetes exacerbates CAD/CAC and intracellular free calcium ([Ca ²⁺] _i) dysregulation in the clinically relevant Ossabaw miniature swine model of MetS.

Methods

Sixteen swine, eight with alloxan-induced diabetes, were fed a hypercaloric, atherogenic diet for 6 months. Alloxan-induced pancreatic beta cell damage was examined by immunohistochemical staining of insulin. The metabolic profile was confirmed by body weight, complete blood panel, intravenous glucose tolerance test (IVGTT), and meal tolerance test. CAD severity was assessed with intravascular ultrasound and histology. [Ca ²⁺] _i handling in coronary smooth muscle (CSM) cells was assessed with fura-2 ratiometric imaging.

Results

Fasting and post-prandial blood glucose, total cholesterol, and serum triglycerides were elevated in MetS-diabetic swine. This group also exhibited hypoinsulinemia during IVGTT and less pancreatic beta cell mass when compared to lean and MetS-nondiabetic swine. IVUS analysis revealed that MetS-diabetic swine had greater percent wall coverage, percent plaque burden, and calcium index when compared to lean and MetS-nondiabetic swine. Fura-2 imaging of CSM [Ca ²⁺] _i revealed that MetS-nondiabetic swine exhibited increased sarcoplasmic reticulum Ca ²⁺ store release and Ca ²⁺ influx through voltage-gated Ca ²⁺ channels compared to lean swine. MetS-diabetic swine exhibited impaired Ca ²⁺ efflux.

Conclusions

Diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with MetS, accompanied by progression of [Ca ²⁺] _i dysregulation in advanced CAD/CAC. These results recapitulate increased CAD in humans with diabetes and establish Ossabaw miniature swine as an animal model for future MetS/diabetes comorbidity studies.

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Most cited references 55

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Detecting human coronary inflammation by imaging perivascular fat.

Suzan Anthony, Marios Margaritis, Laura Herdman … (2017)

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Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue.

Alexios S Antonopoulos, Marios Margaritis, Patricia Coutinho da Silva … (2015)

Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2˙(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2˙(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2˙(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-γ-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.

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Author and article information

Contributors

Jill K. Badin: jbadin@iupui.edu

Ayeeshik Kole: akole@iupui.edu

Benjamin Stivers: bdstiver@umail.iu.edu

Victor Progar: vprogar@umail.iu.edu

Anisha Pareddy: reddy.pareddy@gmail.com

Mouhamad Alloosh: malloosh@iupui.edu

Michael Sturek: 317-274-7772 , msturek@iu.edu

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 9 March 2018

Publication date PMC-release: 9 March 2018

Publication date Collection: 2018

Volume: 16

Electronic Location Identifier: 58

Affiliations

[1 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Cellular & Integrative Physiology, , Indiana University School of Medicine, ; 635 Barnhill Drive, MS 385, Indianapolis, IN 46202-5120 USA

[2 ]ISNI 0000 0004 1937 2197, GRID grid.169077.e, Weldon School of Biomedical Engineering, , Purdue University, ; 206 S Martin Jischke Dr, West Lafayette, IN 47907 USA

Article

Publisher ID: 1431

DOI: 10.1186/s12967-018-1431-9

PMC ID: 5845376

PubMed ID: 29523165

SO-VID: 0052affa-d920-417d-b9f7-3f23bec98fe8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 December 2017

Date accepted : 28 February 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: P30 DK097512

Award ID: HL125385

Award Recipient : Michael Sturek

Funded by: FundRef http://dx.doi.org/10.13039/100006377, Purdue University;

Award ID: Hugh W.

Award ID: Edna M. Donnan Fellowship

Award Recipient : Ayeeshik Kole

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: obesity,metabolism,atherosclerosis,intravascular ultrasound,calcium dysregulation,calcium index

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ScienceOpen disciplines: Medicine

Keywords: obesity, metabolism, atherosclerosis, intravascular ultrasound, calcium dysregulation, calcium index

Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome

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Abstract

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Karger: Nutrition and Dietetics

Most cited references 55

Detecting human coronary inflammation by imaging perivascular fat.

2000 Report of the AVMA Panel on Euthanasia.

Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue.

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