Biology subjects

Borras, C.

Publications and source records attributed to Borras, C..

3 recordsLinked to original sources

bioRxiv2025

Restoring Cholesterol Efflux in Vascular Smooth Muscle Cells Transitioning into Foam Cells Through Liver X Receptor Activation

ObjectiveMacrophage foam cells derived from vascular smooth muscle cells (VSMCs) account for 30-70% of foam cells in atherosclerotic lesions. Liver X receptor (LXR) agonists promote high-density lipoprotein (HDL)-mediated cholesterol efflux from macrophages. This study aimed to investigate the effects of LXR activation on the reverse cholesterol transport (RCT) rate from VSMCs to feces in vivo. Approach and ResultsCholesterol efflux induced by serum and HDL was evaluated in human and mouse VSMCs treated with the LXR agonist T090137 before and after methyl-{beta}-cyclodextrin (MBD)-cholesterol loading. Additional experiments included treatment with an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor. Cholesterol-radiolabeled VSMCs were injected into the peritoneal cavity of mice, and RCT was assessed by measuring radiolabeled cholesterol in serum, liver, and feces over 48 hours. Serum and HDL induced cholesterol efflux at similar levels in both human and mouse VSMCs. Cholesterol efflux was significantly reduced following MBD-cholesterol loading; however, treatment with the LXR agonist significantly enhanced efflux. Radiolabeled foam-like VSMCs injected into mice exhibited impaired cholesterol transfer to serum, HDL, and feces compared to non-lipid-laden VSMCs. Pre-treatment with the LXR agonist increased radiolabeled cholesterol levels in serum and HDL and doubled its fecal excretion. Additionally, LXR activation restored RCT from MBD-cholesterol-loaded VSMCs to feces, reaching levels comparable to those of non-lipid-laden cells. Treatment with an ACAT inhibitor fully restored RCT rates in foam-like VSMCs, and the combination of the ACAT inhibitor and the LXR agonist further enhanced RCT. ConclusionsHDL-mediated cholesterol efflux is significantly impaired in VSMCs during their transition into foam cells. Pharmacological activation of LXR enhances RCT from VSMCs to feces in vivo and restores the impaired RCT from transitioning VSMCs. The combination of LXR agonists and ACAT inhibitors holds promise as a synergistic therapeutic approach to restoring cholesterol homeostasis in lipid-laden VSMCs, offering potential strategies to mitigate atherosclerosis. HighlightsO_LILXR activation enhances cholesterol efflux in VSMCs in vitro, even after their transition into foam cells. C_LIO_LIVSMCs transitioning into foam cells exhibit reduced cholesterol transfer to HDL and feces in mice. C_LIO_LILXR agonist treatment enhances reverse cholesterol transport (RCT) from VSMCs to feces in vivo. C_LIO_LISelective ACAT inhibition restores RCT in foam-like VSMCs, with further enhancement observed upon LXR activation. C_LI

biochemistry↗

bioRxiv2024

Small extracellular vesicles from young adipose-derived stem cells ameliorate age-related changes in the heart of old mice.

BackgroundAging is a process characterized by a progressive decline in physiological functions. This decline contributes to an increased risk of various age-related diseases, including conditions such as heart failure or aortic stenosis. Recent advances have highlighted the potential of stem cell therapies in mitigating the adverse effects of aging. The mechanisms underlying the therapeutic effects of these cells appear to be largely paracrine, including the exchange of different molecules via extracellular vesicles (EVs). This work aims to investigate the potential of sEVs derived from young adipose-derived stem cells (ADSC-sEVs) in restoring structural, molecular, and functional changes associated with aging in the heart. MethodsAged C57BL/6J mice were treated intravenously with ADSC-sEVs from young mice or PBS as controls, young mice were also included to identify specific changes associated with aging. The impact of sEV treatment on cardiac function was assessed using transthoracic echocardiography and physical endurance tests. Histological and molecular analyses were conducted on heart tissue to evaluate structural changes and markers of senescence, inflammation, and oxidative stress. Additionally, a comprehensive metabolomic analysis was performed on heart tissues to identify changes in metabolic profiles associated with aging and treatment status. ResultsAdministration of ADSC-sEVs significantly improves several aging-associated cardiac parameters, including reductions in oxidative stress, inflammation, and cellular senescence. We also report on age-related changes reversal in myocardial structure and function, highlighted by decreased fibrosis and improved vascularization. Notably, echocardiographic assessments reveal that sEV treatments ameliorate diastolic dysfunction and left ventricle structural alterations typically associated with aging. Furthermore, the treatment shifts the heart metabolome towards a more youthful profile. ConclusionsThese results denote the potential of ADSC-sEVs as a novel, non-invasive therapeutic strategy to mitigate cardiac aging-associated functional decline.

physiology↗

bioRxiv2021

Small extracellular vesicles from young mice prevent frailty and improve healthspan in old mice.

Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement. ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSCs-sEVs and their metabolome changed to a youth-like pattern. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

physiology↗