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Differences in the reaction of hyperlipidemia on different endothelial progenitor cells based on sex.

ABSTRACT: The sex of a patient can affect the outcomes of several cardiovascular diseases, and men generally tend to experience earlier episodes of cardiovascular diseases compared with women. The progression of atherosclerosis during hyperlipidemia can be induced by reactive oxygen species (ROS) and oxidized-low-density lipoprotein (ox-LDL). By contrast, bone marrow (BM)-derived endothelial progenitor cells (EPCs) have been reported to serve a protective role against atherosclerosis. The aim of the present was to compare the effects of sex under conditions of hyperlipidemia on different populations of EPCs, and to identify the potential underlying mechanisms. EPC numbers and ROS levels in the blood and BM were measured using fluorescence activated cell sorting in male and female LDL receptor knock-out C57BL/6 mice maintained on a high-fat diet for 6 months, and in male and female wild type C57BL/6 mice following ox-LDL injection for 3 days. Female hyperlipidemic mice exhibited lower levels of plasma lipids, atherosclerotic plaque formation, intracellular EPC ROS formation and inflammatory cytokine levels. Furthermore, BM CD34⁺/ fetal liver kinase-1 (Flk-1⁺), CD34⁺/CD133⁺ and stem cell antigen-1⁺/Flk-1⁺, as well as all circulating EPCs, were maintained at higher levels in female hyperlipidemic mice. In addition, similar changes with regards to BM CD34⁺/Flk-1⁺, CD34⁺/CD133⁺, c-Kit⁺/CD31⁺ and circulating CD34⁺/Flk1⁺ and CD34⁺/CD133⁺ EPCs were observed in female mice following ox-LDL treatment. These sustained higher levels of BM and circulating EPCs in female mice with hyperlipidemia may be associated with reduced levels of ox-LDL as a result of reduced intracellular ROS formation in EPCs and decreased inflammatory cytokine production.

SUBMITTER: Zhuo X

PROVIDER: S-EPMC8212447 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCellular sex has rarely been considered as a biological variable in preclinical research, even when the pathogenesis of diseases with predictable sex differences is studied. In this perspective, proteomics, and "omics" approaches in general, can provide powerful tools to obtain comprehensive cellular maps, thus favoring the discovery of still unknown sex-biased physio-pathological mechanisms.MethodsWe performed proteomic and Gene Ontology (GO) analyses of the secretome from human serum-deprived male and female endothelial cells (ECs) followed by ELISA validation. Apoptosis was detected by FACS and Western blot techniques and efferocytosis through the ability of the macrophage cell line RAW 264.7 to engulf apoptotic ECs. PTX3 mRNA levels were measured by RT-qPCR.ResultsProteomic and GO analyses of the secretome from starved human male and female ECs demonstrated a significant enrichment in proteins related to cellular responses to stress and to the regulation of apoptosis in the secretome of male ECs. Accordingly, a higher percentage of male ECs underwent apoptosis in response to serum deprivation in comparison with female ECs. Among the secreted proteins, we reliably found higher levels of PTX3 in the male EC secretome. The silencing of PTX3 suggested that male ECs were dependent on its expression to properly carry out the efferocytotic process. At variance, female EC efferocytosis seemed to be independent on PTX3 expression.ConclusionsOur results demonstrated that serum-starved male and female ECs possess different secretory phenotypes that might take part in the sex-biased response to cellular stress. We identified PTX3 as a crucial player in the male-specific endothelial response to an apoptotic trigger. This novel and sex-related role for secreted proteins, and mainly for PTX3, may open the way to the discovery of still unknown sex-specific mechanisms and pharmacological targets for the prevention and treatment of endothelial dysfunction at the onset of atherosclerosis and cardiovascular disease.

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Differences in the reaction of hyperlipidemia on different endothelial progenitor cells based on sex.

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