Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia

Oana Sorop, Mieke van den Heuvel, Nienke S. van Ditzhuijzen, Vincent J. de Beer, Ilkka Heinonen, Richard W.B. van Duin, Zhichao Zhou, Sietse J. Koopmans, Daphne Merkus, Wim J. van der Giessen

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Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)-and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted brady-kinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD. n = 5). Responses of small (~300-μm-diameter) coronary arteries to BK. ET-1. and the nitric oxide (NO) donor 5-nitroso-N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine (n = 12). Blood glucose was elevated in DM + HFD (17.6 ± 4.5 mmol/1) compared with HFD (5.1 ± 0.4 mmol/1) and Normal (5.8 ± 0.6 mmol/1) swine, while cholesterol was markedly elevated in DM + HFD (16.8 ± 1.7 mmol/1) and HFD (18.1 ±2.6 mmol/1) compared with Normal (2.1 ± 0.2 mmol/1) swine (all P <0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly. DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P <0.05), resulting mainly from ΕΤ» receptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P <0.05). In conclusion. 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-de-rived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ΕΤB receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.

Original languageEnglish
Pages (from-to)H1339-H1351
JournalAmerican Journal of Physiology : Heart and Circulatory Physiology
Issue number6
Publication statusPublished - 2016


  • Coronary microvascular dysfunction
  • Diabetes
  • Endothelin-1
  • Hypercholesterolemia
  • Swine

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    Sorop, O., van den Heuvel, M., van Ditzhuijzen, N. S., de Beer, V. J., Heinonen, I., van Duin, R. W. B., Zhou, Z., Koopmans, S. J., Merkus, D., & van der Giessen, W. J. (2016). Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia. American Journal of Physiology : Heart and Circulatory Physiology, 311(6), H1339-H1351.