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Deficiency of T-type voltage-gated calcium channels results in attenuated weight gain and improved endothelium-dependent dilatation of resistance vessels induced by a high-fat diet in mice

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Abstract

The deletion of T-type Cav3.1 channels may reduce high-fat diet (HFD)-induced weight gain, which correlates positively with obesity and endothelial dysfunction. Therefore, experiments were designed to study the involvement of T-type Cav3.1 channels in HFD-induced endothelial dysfunction in mice. Wildtype (WT) and Cav3.1−/− mice were fed either a normal diet (ND) or an HFD for 8 weeks. Body composition was assessed, and thoracic aortae and mesenteric arteries were harvested for myography to assess endothelium-dependent responses. Changes in intracellular calcium were measured by fluorescence imaging, and behavior was assessed with the open-field test. Cav3.1−/− mice had attenuated HFD-induced weight gain and lower total fat mass compared with WT mice. Cav3.1−/− mice on an HFD had reduced plasma cholesterol levels compared with WT mice on the same diet. Increased feeding efficiency, independent of food intake, was observed in WT mice on an HFD compared with an ND, but no difference in feeding efficiency between diets was observed for Cav3.1−/− mice. Nitric oxide-dependent dilatation was increased in mesenteric arteries of Cav3.1−/− mice compared with WT mice on an HFD, with no difference observed in aortae. No differences in mouse locomotor activity were observed between the experimental groups. Mice on an HFD lacking T-type channels have reduced weight gain, lower total cholesterol levels, and increased dilatation of resistance vessels compared with WT mice on an HFD, suggesting that Cav3.1 deletion protects against endothelial dysfunction in resistance vessels but not in large conduit vessels.

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Acknowledgements

We would like to thank Vivi Monrad for expert technical assistance.

Funding

This work was supported by grants from the Novo Nordisk Foundation (13273), the Danish Medical Research Council (11-107552), and the Danish Heart Foundation (11-04-R84-A3492-22663).

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Authors and Affiliations

  1. Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark

    Kristoffer Rosenstand, Kenneth Andersen, Rasmus Terp, Pernille B. L. Hansen & Per Svenningsen

  2. Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Peter Gennemark, Anna Reznichenko & Pernille B. L. Hansen

  3. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Ditte Gry Ellman & Kate Lykke Lambertsen

  4. Department of Neurology, Odense University Hospital, Odense, Denmark

    Kate Lykke Lambertsen

  5. BRIDGE, Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Kate Lykke Lambertsen

  6. State Key Laboratory for Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong, China

    Paul M. Vanhoutte

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  1. Kristoffer Rosenstand
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Contributions

Conceived of or designed study: PBLH; Performed research: KR, KA, RT, DGE, AR; Analyzed data: KR, KA, RT, PG, DGE, AR, KLL, PMV, PS, PBLH; Contributed new methods or models and wrote the paper: PBLH with input from PS and PMV

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Correspondence to Per Svenningsen.

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Key points

•Cav3.1 deficiency protects against high fat diet-induced weight gain.

•Cav3.1 deficiency protects against high fat diet-induced endothelial dysfunction.

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Rosenstand, K., Andersen, K., Terp, R. et al. Deficiency of T-type voltage-gated calcium channels results in attenuated weight gain and improved endothelium-dependent dilatation of resistance vessels induced by a high-fat diet in mice. J Physiol Biochem 76, 135–145 (2020). https://doi.org/10.1007/s13105-020-00728-2

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