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Mechanism of the switch from NO to H2O2 in endothelium-dependent vasodilation in diabetes

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Abstract

Coronary microvascular dysfunction is prevalent among people with diabetes and is correlated with cardiac mortality. Compromised endothelial-dependent dilation (EDD) is an early event in the progression of diabetes, but its mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelium-dependent vasodilatory metabolite in the healthy coronary circulation, but this switches to hydrogen peroxide (H2O2) in coronary artery disease (CAD) patients. Because diabetes is a significant risk factor for CAD, we hypothesized that a similar NO-to-H2O2 switch would occur in diabetes. Vasodilation was measured ex vivo in isolated coronary arteries from wild type (WT) and microRNA-21 (miR-21) null mice on a chow or high-fat/high-sugar diet, and B6.BKS(D)-Leprdb/J (db/db) mice using myography. Myocardial blood flow (MBF), blood pressure, and heart rate were measured in vivo using contrast echocardiography and a solid-state pressure sensor catheter. RNA from coronary arteries, endothelial cells, and cardiac tissues was analyzed via quantitative real-time PCR for gene expression, and cardiac protein expression was assessed via western blot analyses. Superoxide was detected via electron paramagnetic resonance. (1) Ex vivo coronary EDD and in vivo MBF were impaired in diabetic mice. (2) Nω-Nitro-L-arginine methyl ester, an NO synthase inhibitor (L-NAME), inhibited ex vivo coronary EDD and in vivo MBF in WT. In contrast, polyethylene glycol-catalase, an H2O2 scavenger (Peg-Cat), inhibited diabetic mouse EDD ex vivo and MBF in vivo. (3) miR-21 was upregulated in diabetic mouse endothelial cells, and the deficiency of miR-21 prevented the NO-to-H2O2 switch and ameliorated diabetic mouse vasodilation impairments. (4) Diabetic mice displayed increased serum NO and H2O2, upregulated mRNA expression of Sod1, Sod2, iNos, and Cav1, and downregulated Pgc-1α in coronary arteries, but the deficiency of miR-21 reversed these changes. (5) miR-21-deficient mice exhibited increased cardiac PGC-1α, PPARα and eNOS protein and reduced endothelial superoxide. (6) Inhibition of PGC-1α changed the mRNA expression of genes regulated by miR-21, and overexpression of PGC-1α decreased the expression of miR-21 in high (25.5 mM) glucose treated coronary endothelial cells. Diabetic mice exhibit a NO-to-H2O2 switch in the mediator of coronary EDD, which contributes to microvascular dysfunction and is mediated by miR-21. This study represents the first mouse model recapitulating the NO-to-H2O2 switch seen in CAD patients in diabetes.

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Acknowledgements

We would like to thank Laura Zhang for illustrating Supplementary Figure 3.

Funding

This research is funded by National Institutes of Health grant 2R01HL103227-05 (YZ, LY), 1R01HL135110-01 (WMC, LY), 1 R01 HL137008-01A1 (LY), and F31HL156726 (CJ).

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  1. Cody Juguilon, Zhiyuan Wang and Yang Wang are co-first authors.

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  1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA

    Cody Juguilon, Zhiyuan Wang, Yang Wang, Molly Enrick, Anurag Jamaiyar, Yanyong Xu, James Gadd, Chwen-Lih W. Chen, Autumn Pu, Chris Kolz, Vahagn Ohanyan, Yeong-Renn Chen, James Hardwick, Yanqiao Zhang, William M. Chilian & Liya Yin

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  1. Cody Juguilon
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Correspondence to Liya Yin.

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The previous version of this manuscript (R1) was uploaded to bioRxiv (https://doi.org/10.1101/2021.05.18.444667).

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Juguilon, C., Wang, Z., Wang, Y. et al. Mechanism of the switch from NO to H2O2 in endothelium-dependent vasodilation in diabetes. Basic Res Cardiol 117, 2 (2022). https://doi.org/10.1007/s00395-022-00910-1

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  • DOI: https://doi.org/10.1007/s00395-022-00910-1

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