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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2018

Open Access 01-12-2018 | Research

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

Authors: Jill K. Badin, Ayeeshik Kole, Benjamin Stivers, Victor Progar, Anisha Pareddy, Mouhamad Alloosh, Michael Sturek

Published in: Journal of Translational Medicine | Issue 1/2018

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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 ([Ca2+]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. [Ca2+]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 [Ca2+]i revealed that MetS-nondiabetic swine exhibited increased sarcoplasmic reticulum Ca2+ store release and Ca2+ influx through voltage-gated Ca2+ channels compared to lean swine. MetS-diabetic swine exhibited impaired Ca2+ efflux.

Conclusions

Diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with MetS, accompanied by progression of [Ca2+]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.
Literature
1.
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, et al. Heart disease and stroke statistics-2016 update: a report from the American heart association. Circulation. 2016;133:e38–60.CrossRefPubMed
2.
Karwowski W, Naumnik B, Szczepanski M, Mysliwiec M. The mechanism of vascular calcification—a systematic review. Med Sci Monit. 2012;18:1–11.CrossRef
3.
Kim JY, Mun HS, Lee BK, Yoon SB, Choi EY, Min PK, Yoon YW, Hong BK, Rim SJ, Kwon HM. Impact of metabolic syndrome and its individual components on the presence and severity of angiographic coronary artery disease. Yonsei Med J. 2010;51:676–82.CrossRefPubMedPubMedCentral
4.
Alexander CM, Landsman PB, Teutsch SM, Haffner SM, Third National H, Nutrition Examination S. National cholesterol education P: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210–4.CrossRefPubMed
5.
Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab. 2004;89:2601–7.CrossRefPubMed
6.
Nicholls SJ, Tuzcu EM, Kalidindi S, Wolski K, Moon KW, Sipahi I, Schoenhagen P, Nissen SE. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling: a pooled analysis of 5 intravascular ultrasound trials. J Am Coll Cardiol. 2008;52:255–62.CrossRefPubMed
7.
Bayturan O, Tuzcu EM, Lavoie A, Hu T, Wolski K, Schoenhagen P, Kapadia S, Nissen SE, Nicholls SJ. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med. 2010;170:478–84.CrossRefPubMed
8.
Gerrity RG, Natarajan R, Nadler JL, Kimsey T. Diabetes-induced accelerated atherosclerosis in swine. Diabetes. 2001;50:1654–65.CrossRefPubMed
9.
Al-Mashhadi RH, Bjorklund MM, Mortensen MB, Christoffersen C, Larsen T, Falk E, Bentzon JF. Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs. Diabetologia. 2015;58:1926–36.CrossRefPubMed
10.
Dixon JL, Stoops JD, Parker JL, Laughlin MH, Weisman GA, Sturek M. Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet. Arterioscler Thromb Vasc Biol. 1999;19:2981–92.CrossRefPubMed
11.
Lee DL, Wamhoff BR, Katwa LC, Reddy HK, Voelker DJ, Dixon JL, Sturek M. Increased endothelin-induced Ca2+ signaling, tyrosine phosphorylation, and coronary artery disease in diabetic dyslipidemic swine are prevented by atorvastatin. J Pharmacol Exp Ther. 2003;306:132–40.CrossRefPubMed
12.
Ludvigsen TP, Kirk RK, Christoffersen BO, Pedersen HD, Martinussen T, Kildegaard J, Heegaard PM, Lykkesfeldt J, Olsen LH. Gottingen minipig model of diet-induced atherosclerosis: influence of mild streptozotocin-induced diabetes on lesion severity and markers of inflammation evaluated in obese, obese and diabetic, and lean control animals. J Transl Med. 2015;13:312.CrossRefPubMedPubMedCentral
13.
Mokelke EA, Hu Q, Song M, Toro L, Reddy HK, Sturek M. Altered functional coupling of coronary K+ channels in diabetic dyslipidemic pigs is prevented by exercise. J Appl Physiol. 2003;95:1179–93.CrossRefPubMed
14.
Dyson MC, Alloosh M, Vuchetich JP, Mokelke EA, Sturek M. Components of metabolic syndrome and coronary artery disease in female Ossabaw swine fed excess atherogenic diet. Comp Med. 2006;56:35–45.PubMed
15.
Kreutz RP, Alloosh M, Neeb ZP, Kreutz Y, Flockhart DA, Sturek M. Metabolic syndrome in Ossabaw miniature swine is associated with increased sensitivity of platelet aggregation to adenosine diphosphate (abstract). ATVB. 2009;29:e122.
16.
Lee L, Alloosh M, Saxena R, Van Alstine W, Watkins BA, Klaunig JE, Sturek M, Chalasani N. Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Hepatology. 2009;50:56–67.CrossRefPubMedPubMedCentral
17.
McKenney-Drake ML, Territo PR, Salavati A, Houshmand S, Persohn S, Liang Y, Alloosh M, Moe SM, Weaver CM, Alavi A, Sturek M. 18F-NaF PET imaging of early coronary artery calcification. JACC Cardiovasc Imaging. 2016;9:627–8.CrossRefPubMed
18.
McKenney-Drake ML, Rodenbeck SD, Owen MK, Schultz KA, Alloosh M, Tune JD, Sturek M. Biphasic alterations in coronary smooth muscle Ca2+ regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome. Atherosclerosis. 2016;249:1–9.CrossRefPubMedPubMedCentral
19.
Phillips-Eakley AK, McKenney-Drake ML, Bahls M, Newcomer SC, Radcliffe JS, Wastney ME, Van Alstine WG, Jackson G, Alloosh M, Martin BR, et al. Effect of high-calcium diet on coronary artery disease in Ossabaw miniature swine with metabolic syndrome. JAHA. 2015;4(8):e001620.PubMedPubMedCentral
20.
Sturek M, Tune JD, Alloosh M. Ossabaw Island miniature swine: metabolic syndrome and cardiovascular assessment. In: Swindle MM, editor. Swine in the laboratory: surgery, anesthesia, imaging, and experimental techniques. 3rd ed. Boca Raton: CRC Press; 2015. p. 451–65.CrossRef
21.
Wastney M, Lee W, Jackson GS, Alloosh M, Sturek M, Lachcik P, Peacock M, Martin B, Weaver CM. Soft tissue calcification in the Ossabaw miniature pig: experimental and kinetic modeling studies. Osteoporos Int. 2013;24:2123–6.CrossRefPubMed
22.
Neeb ZP, Edwards JM, Alloosh M, Long X, Mokelke EA, Sturek M. Metabolic syndrome and coronary artery disease in Ossabaw compared with Yucatan swine. Comp Med. 2010;60:300–15.PubMedPubMedCentral
23.
AVMA Panel on Euthanasia. American veterinary medical association: 2000 report of the AVMA panel on euthanasia. JAVMA. 2001;218:669–96.CrossRef
24.
Institute for Laboratory Animal Research. Guide for the care and use of laboratory animals. 8th ed. Washington, D.C.: National Academy Press; 2010.
25.
Boullion RD, Mokelke EA, Wamhoff BR, Otis CR, Wenzel J, Dixon JL, Sturek M. Porcine model of diabetic dyslipidemia: insulin and feed algorithms for mimicking diabetes in humans. Comp Med. 2003;53:42–52.PubMed
26.
Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. Group Ac-DAGS: translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:1473–8.CrossRefPubMedPubMedCentral
27.
28.
Witczak CA, Wamhoff BR, Sturek M. Exercise training prevents Ca2+ dysregulation in coronary smooth muscle from diabetic dyslipidemic Yucatan swine. J Appl Physiol. 2006;101:752–62.CrossRefPubMed
29.
Edwards JM, Neeb ZP, Alloosh MA, Long X, Bratz IN, Peller CR, Byrd JP, Kumar S, Obukhov AG, Sturek M. Exercise training decreases store-operated Ca2+ entry associated with metabolic syndrome and coronary atherosclerosis. Cardiovasc Res. 2010;85:631–40.CrossRefPubMed
30.
Heaps CL, Sturek M, Price EM, Laughlin MH, Parker JL. Sarcoplasmic reticulum Ca(2+) uptake is impaired in coronary smooth muscle distal to coronary occlusion. Am J Physiol Heart Circ Physiol. 2001;281:H223–31.CrossRefPubMed
31.
Ehara S, Kobayashi Y, Yoshiyama M, Ueda M, Yoshikawa J. Coronary artery calcification revisited. J Atheroscler Thromb. 2006;13:31–7.CrossRefPubMed
32.
Tamaru H, Fujii K, Fukunaga M, Imanaka T, Miki K, Horimatsu T, Nishimura M, Saita T, Sumiyoshi A, Shibuya M, et al. Impact of spotty calcification on long-term prediction of future revascularization: a prospective three-vessel intravascular ultrasound study. Heart Vessels. 2016;31:881–9.CrossRefPubMed
33.
Elmadhun NY, Sabe AA, Lassaletta AD, Chu LM, Kondra K, Sturek M, Sellke FW. Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium. J Thorac Cardiovasc Surg. 2014;148:1048–55.CrossRefPubMedPubMedCentral
34.
Kreutz RP, Alloosh M, Mansour K, Neeb Z, Kreutz Y, Flockhart DA, Sturek M. Morbid obesity and metabolic syndrome in Ossabaw miniature swine are associated with increased platelet reactivity. Diabetes Metab Syndr Obes. 2011;4:99–105.CrossRefPubMedPubMedCentral
35.
Liang T, Alloosh M, Bell LN, Fullenkamp AM, Saxena R, Van Alstine W, Bybee P, Werling K, Sturek M, Chalasani N, Masuoka HC. Liver injury and fibrosis induced by dietary challenge in the Ossabaw miniature swine. PLoS ONE. 2015;10(5):e0124173.CrossRefPubMedPubMedCentral
36.
Newell-Fugate AE, Taibl JN, Alloosh M, Sturek M, Bahr JM, Nowak RA, Krisher RL. Effects of obesity and metabolic syndrome on steroidogenesis and folliculogenesis in the female Ossabaw mini-pig. PLoS ONE. 2015;10:e0128749.CrossRefPubMedPubMedCentral
37.
Newell-Fugate AE, Taibl JN, Clark SG, Alloosh M, Sturek M, Krisher RL. Effects of diet-induced obesity on metabolic parameters and reproductive function in female Ossabaw minipigs. Comp Med. 2014;64:44–9.PubMedPubMedCentral
38.
Fullenkamp AM, Bell LN, Robbins RD, Lee L, Saxena R, Alloosh M, Klaunig JE, Mirmira RG, Sturek M, Chalasani N. Effect of different obesogenic diets on pancreatic histology in Ossabaw miniature swine. Pancreas. 2011;40:438–43.CrossRefPubMedPubMedCentral
39.
Veiraiah A. Hyperglycemia, lipoprotein glycation, and vascular disease. Angiology. 2005;56:431–8.CrossRefPubMed
40.
Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des. 2005;11:2279–99.CrossRefPubMed
41.
Southerland JH, Taylor GW, Moss K, Beck JD, Offenbacher S. Commonality in chronic inflammatory diseases: periodontitis, diabetes, and coronary artery disease. Periodontol. 2000;2006(40):130–43.
42.
Stolar M. Glycemic control and complications in type 2 diabetes mellitus. Am J Med. 2010;123:S3–11.CrossRefPubMed
43.
Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res. 1987;28:613–28.PubMed
44.
Antonopoulos AS, Margaritis M, Coutinho P, Shirodaria C, Psarros C, Herdman L, Sanna F, De Silva R, Petrou M, Sayeed R, et al. 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. Diabetes. 2015;64:2207–19.CrossRefPubMed
45.
McKenney ML, Schultz KA, Boyd JH, Byrd JP, Alloosh M, Teague SD, Arce-Esquivel AA, Fain JN, Laughlin MH, Sacks HS, Sturek M. Epicardial adipose excision slows the progression of porcine coronary atherosclerosis. J Cardiothorac Surg. 2014;9:2–12.CrossRefPubMedPubMedCentral
46.
McKenney-Drake ML, Rodenbeck SD, Bruning RS, Kole A, Yancey KW, Alloosh M, Sacks HS, Sturek M. Epicardial adipose tissue removal potentiates outward remodeling and arrests coronary atherogenesis. Ann Thorac Surg. 2017;103:1622–30.CrossRefPubMed
47.
Antonopoulos AS, Sanna F, Sabharwal N, Thomas S, Oikonomou EK, Herdman L, Margaritis M, Shirodaria C, Kampoli AM, Akoumianakis I, et al. Detecting human coronary inflammation by imaging perivascular fat. Sci Transl Med. 2017;9(398):58.CrossRef
48.
Owen MK, Witzmann FA, McKenney ML, Lai X, Berwick ZC, Moberly SP, Alloosh M, Sturek M, Tune JD. Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: influence of obesity. Circulation. 2013;128:9–18.CrossRefPubMedPubMedCentral
49.
Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M, Tune JD. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol. 2010;30:1711–7.CrossRefPubMedPubMedCentral
50.
Khazai B, Luo Y, Rosenberg S, Wingrove J, Budoff MJ. Coronary atherosclerotic plaque detected by computed tomographic angiography in subjects with diabetes compared to those without diabetes. PLoS ONE. 2015;10:e0143187.CrossRefPubMedPubMedCentral
51.
Cao Y, Kole A, Hui J, Zhang Y, Mai J, Alloosh M, Sturek M, Cheng J-X. Fast assessment of lipid content in arteries in vivo by intravascular photoacoustic tomography. Sci Rep. 2018;8(1):2400.CrossRefPubMedPubMedCentral
52.
Hui J, Cao Y, Zhang Y, Kole A, Wang P, Yu G, Eakins G, Sturek M, Chen W, Cheng J-X. Real-time intravascular photoacoustic-ultrasound imaging of lipid-laden plaque in human coronary artery at 16 frames per second. Sci Rep. 2017;7:1417.CrossRefPubMedPubMedCentral
53.
Cao Y, Kole A, Lan L, Wang P, Hui J, Sturek M, Cheng J-X. Spectral analysis assisted photoacoustic imaging for lipid composition differentiation. Photoacoustics. 2017;7:12–9.CrossRefPubMedPubMedCentral
54.
Hui J, Li R, Phillips EH, Goergen CJ, Sturek M, Cheng J-X. Bond-selective photoacoustic imaging by converting molecular vibration into mechanical waves. Photoacoustics. 2016;4:11–21.CrossRefPubMedPubMedCentral
55.
Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84:767–801.CrossRefPubMed
56.
57.
House SJ, Potier M, Bisaillon J, Singer HA, Trebak M. The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers Arch. 2008;456:769–85.CrossRefPubMedPubMedCentral
58.
Pauly RR, Bilato C, Sollott SJ, Monticone R, Kelly PT, Lakatta EG, Crow MT. Role of calcium/calmodulin-dependent protein kinase II in the regulation of vascular smooth muscle cell migration. Circulation. 1995;91:1107–15.CrossRefPubMed
59.
Lundberg MS, Curto KA, Bilato C, Monticone RE, Crow MT. Regulation of vascular smooth muscle migration by mitogen-activated protein kinase and calcium/calmodulin-dependent protein kinase II signaling pathways. J Mol Cell Cardiol. 1998;30:2377–89.CrossRefPubMed
60.
61.
Wamhoff BR, Bowles DK, McDonald OG, Sinha S, Somlyo AP, Somlyo AV, Owens GK. L-type voltage-gated Ca2+ channels modulate expression of smooth muscle differentiation marker genes via a rho kinase/myocardin/SRF-dependent mechanism. Circ Res. 2004;95:406–14.CrossRefPubMed
62.
Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011;109:697–711.CrossRefPubMedPubMedCentral
63.
Chen NX, Kircelli F, O’Neill KD, Chen X, Moe SM. Verapamil inhibits calcification and matrix vesicle activity of bovine vascular smooth muscle cells. Kidney Int. 2010;77:436–42.CrossRefPubMed
64.
Kataoka Y, Wolski K, Uno K, Puri R, Tuzcu EM, Nissen SE, Nicholls SJ. Spotty calcification as a marker of accelerated progression of coronary atherosclerosis: insights from serial intravascular ultrasound. J Am Coll Cardiol. 2012;59:1592–7.CrossRefPubMed
65.
Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D, Nakamura Y, Yamashita H, Yamagishi H, Takeuchi K, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction. Circulation. 2004;110:3424–9.CrossRefPubMed
66.
Amano H, Ikeda T, Toda M, Okubo R, Yabe T, Koike M, Saito D, Yamazaki J. Assessment of angiographic coronary calcification and plaque composition in virtual histology intravascular ultrasound. J Interv Cardiol. 2015;28:205–14.CrossRefPubMed
Metadata
Title
Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome
Authors
Jill K. Badin
Ayeeshik Kole
Benjamin Stivers
Victor Progar
Anisha Pareddy
Mouhamad Alloosh
Michael Sturek
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2018
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-018-1431-9

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