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Assessment of the mechanisms of flow-induced dilation of carotid artery in low salt and high salt fed Tff3−/−/C57BL/6N mice and their wild type controls

Introduction:. This study aimed to assess the effects of HS diet on the mechanisms of flow- induced dilation (FID) in isolated, pressurized carotid arteries of Tff3-/- knockout mice and their wild type controls, C57BL/6N mice. Methods: Male, ten-weeks-old transgenic Tff3−/ −/C57BL/6N (Tff3−/−) knockout mice and WT/C57BL/6N (WT) (parental strain) healthy mice were divided to low salt (LS ; 0.4% NaCl in rodent chow) and HS (4% NaCl in rodent chow) groups, fed for 1 week, water ad libidum. The mice were anesthetized with ketamine-chloride (100 mg/kg) and midazolam (5 mg/kg) and decapitated. Carotid arteries were isolated, cannulated and pressurized for 60’at 100 mmHg to assess basal diameter and then subjected to flow at pressure gradients Δ10-Δ180 mmHg (DMT pressure myograph, Danmark). FID was determined in the presence of Nω-nitro-L-arginine methyl ester (L-NAME ; 10–4M ; NO synthase (NOS) inhibitor), the cyclooxygenase inhibitor indomethacin (INDO ; 10-5M) and the CYP450-epoxygenase inhibitor (MS-PPOH ; 10-5M). Statistical analyses were performed with Two-way ANOVA tests ; p<0.05 was considered significant. Results: FID was similar between the Tff3−/−_LS and Tff3−/−_HS groups, while WT_ HS mice exhibited significantly reduced FID compared to WT_LS group. FID was significanty reduced in Tff3−/−_LS compared to WT_LS mice. In Tff3-/-_ LS group L-NAME, INDO and MS-PPOH significantly reduced FID at each pressure gradient. In Tff3-/- _HS group only INDO reduced FID at ∆120, 140 and 160 mm Hg. In WT_LS group and WT_HS group all inhibitors reduced FID at ∆100-180 mm Hg, except in WT_LS group at ∆100 mmHg where only MS-PPOH had effect. Discussion: The impaired vascular endothelium- dependent responses to FID are caused by high salt (HS) diet. Metabolites of arachidonic acid (AA) play role in the mechanisms of vasorelaxation, as well as NO. Conclusion: HS diet significantly impairs vasorelaxation in WT mice. Deletion of Tff3-/- gene may attenuate vasorelaxation, mechanisms of which are affected by HS intake. Ethical Committee: All experimental procedures conformed to the European Guidelines for the Care and Use of Laboratory Animals (directive 86/609) and were approved by the local and national Ethical Committee (No. 2158/61-02-139/2-06 and No. 2158/61-07-14-119). Acknowledgements: This study was supported by the Croatian Science Foundation under the project IP- 2014-09-6380 (V-ELI Athero), VIF-2018-MEFOS-09- 1509 grant and Faculty of Medicine Osijek Institutional grant #IP-1 (2019 ; PI Ines Drenjančević). Thank to Cedars - Sinai Medical Center’s International Research and Innovation in Medicine Program, the Association for Regional Cooperation in the Fields of Health, Science and Technology (RECOOP HST Association) for their support of our organization as participating Cedars – Sinai Medical Center - RECOOP Research Centers (CRRC). Session: cardiovascular diseases (CVD)

Tff3 gene, oxidative stress, high salt diet

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