TUDCA treatment restores early protein-restriction-induced aortic hipocontractility and endothelial dysfunction

TUDCA treatment restores early protein-restriction-induced aortic hipocontractility and endothelial dysfunction Israelle Netto Freitas1,2; Joel da Silva Junior2; Jamaira Aparecida Victorio1,2; Everardo Magalhães Carneiro1,2; Ana Paula Davel1 1Laboratory of Vascular Biology and 2Obesity and Comorbidities Center-OCRC, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, Brazil. Malnutrition is a risk factor for the development of vascular dysfunction. Tauroursodeoxycholic acid (TUDCA) inhibits endoplasmic reticulum stress (ERS) and has been demonstrated to be protective against vascular dysfunction in cardiometabolic diseases. Therefore, we hypothesized that TUDCA could be beneficial for endothelial function and vascular contractility during malnutrition. For this, post-weaning male and female mice fed a normoprotein (NP, 14% protein) or low protein (LP, 6% protein, isocaloric) diet for 15 weeks. In the last 2 weeks, some NP and LP animals received TUDCA (300 mg/kg/day, ip) or vehicle. At the end of the treatment, body weight (BW) and systolic blood pressure (SBP) were evaluated and thoracic aortic isolated to assess vascular responses, fluorescence to dihydroethidium (DHE) and gene expression. As results, BW was reduced and SBP was elevated in male and female protein-restricted groups; TUDCA treatment restored SBP but not BW. Only in males, protein restriction impaired endothelium-dependent relaxation to acetylcholine and reduced contractility (phenylephrine, serotonin, and TXA2 analogue U46619) in aorta. TUDCA reversed both endothelial dysfunction and hypocontractility in LP male group. We found reduced expression of smooth muscle 22α (SM22α), α-actin and L-type calcium channel (Cav1.2) in aorta from male LP compared to NP, which was restored by TUDCA treatment. In addition, aorta from male LP group showed increased DHE fluorescence and gene expression of the ERS markers GRP78, ATF6, PERK, IRE1α and CHOP. These alterations were reversed by TUDCA. In conclusion, our data suggest that post-weaning protein restriction results in endothelial dysfunction and aortic hypocontractility in males only. These alterations were associated with oxidative stress and reduced expression of vascular contractile and ERS markers. TUDCA treatment rescued vascular contraction and endothelial function in early protein-restricted mice evidencing the therapeutic potential of this bile acid for the vascular complications associated with undernutrition. The authors have nothing to disclose. Funding source: São Paulo Research Foundation (FAPESP). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.