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CPT1A expression was downregulated during endothelial senescence in vitro and in vivo. CPT1A protein expression was measured by Western blot in (a) H2O2-induced senescent endothelial cells and (b) replicative senescent endothelial cells. n=3. Data were presented as means±SEM. ∗P<0.05 vs. control/young. Immunofluorescent staining of CPT1A was performed in the frozen aortic sections of (c) SHRs and their normotensive control WKY rats and (d) mice infused with or without Ang II for 4 weeks. CD31 represented the endothelial layer. DAPI represents cell nucleus of the vasculature. Merge of CD31 (green) and CPT1A (red) was shown in yellow and indicated the expression of CPT1A in the endothelial layer. n=4.
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Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endo...
Citations
... Second, CD36-dependent endothelial fatty acid transport alterations have been implicated in metabolic abnormalities and cardiovascular disease [91]. Third, the role of carnitine palmitoyl transferase alterations in endothelial dysfunction has been reported [81,92]. Finally, it has been suggested that mitochondrial dysfunction can drive metabolic reprogramming of vascular endothelial cells in pulmonary hypertension and other cardiovascular conditions; however, these pathways are incompletely characterized [93]. ...
... Second, metabolic pathways can be targeted by metformin [98] and an inducer of fatty acid oxidation, PPARα agonist fenofibrate [99]. Meanwhile, it is still debated whether inhibiting fatty acid oxidation in endothelial cells causes cell senescence or can potentially promote endothelial cell proliferation [92,99]. Specific defects in vascular mitochondrial fatty acid oxidation are still elusive, and additional studies can potentially uncover novel therapeutic approaches to correct these metabolic defects in endothelial and vascular dysfunction. ...
There is a “popular” belief that a fat-free diet is beneficial, supported by the scientific dogma indicating that high levels of fatty acids promote many pathological metabolic, cardiovascular, and neurodegenerative conditions. This dogma pressured scientists not to recognize the essential role of fatty acids in cellular metabolism and focus on the detrimental effects of fatty acids. In this work, we critically review several decades of studies and recent publications supporting the critical role of mitochondrial fatty acid metabolism in cellular homeostasis and many pathological conditions. Fatty acids are the primary fuel source and essential cell membrane building blocks from the origin of life. The essential cell membranes phospholipids were evolutionarily preserved from the earlier bacteria in human subjects. In the past century, the discovery of fatty acid metabolism was superseded by the epidemic growth of metabolic conditions and cardiovascular diseases. The association of fatty acids and pathological conditions is not due to their “harmful” effects but rather the result of impaired fatty acid metabolism and abnormal lifestyle. Mitochondrial dysfunction is linked to impaired metabolism and drives multiple pathological conditions. Despite metabolic flexibility, the loss of mitochondrial fatty acid oxidation cannot be fully compensated for by other sources of mitochondrial substrates, such as carbohydrates and amino acids, resulting in a pathogenic accumulation of long-chain fatty acids and a deficiency of medium-chain fatty acids. Despite popular belief, mitochondrial fatty acid oxidation is essential not only for energy-demanding organs such as the heart, skeletal muscle, and kidneys but also for metabolically “inactive” organs such as endothelial and epithelial cells. Recent studies indicate that the accumulation of long-chain fatty acids in specific organs and tissues support the impaired fatty acid oxidation in cell- and tissue-specific fashion. This work, therefore, provides a basis to challenge these established dogmas and articulate the need for a paradigm shift from the “pathogenic” role of fatty acids to the critical role of fatty acid oxidation. This is important to define the causative role of impaired mitochondrial fatty acid oxidation in specific pathological conditions and develop novel therapeutic approaches targeting mitochondrial fatty acid metabolism.
... Consequently, the heightened glucose consumption in senescent ECs may not be directly linked to redox regulation or nucleotide synthesis (295). Lin et al. (2022) conducted a study to investigate the role of fatty acid metabolism in EC senescence. Using replicative and H 2 O 2 -induced senescence models in human umbilical vein ECs (HUVECs), they observed suppressed FAO and disrupted fatty acid profiles, along with reduced expression of proteins involved in fatty acid uptake and mitochondrial entry, including CPT1A. ...
Endothelial cell (EC) senescence is increasingly recognized as a significant contributor to the development of vascular dysfunction and age-related disorders and diseases, including cancer and cardiovascular diseases (CVD). The regulation of cellular senescence is known to be influenced by cellular metabolism. While extensive research has been conducted on the metabolic regulation of senescence in other cells such as cancer cells and fibroblasts, our understanding of the metabolic regulation of EC senescence remains limited. The specific metabolic changes that drive EC senescence are yet to be fully elucidated. The objective of this review is to provide an overview of the intricate interplay between cellular metabolism and senescence, with a particular emphasis on recent advancements in understanding the metabolic changes preceding cellular senescence. I will summarize the current knowledge on the metabolic regulation of EC senescence, aiming to offer insights into the underlying mechanisms and future research directions.
... Chen et al. discovered that acetic acid promotes VEC senescence by enhancing the interaction between the SESAME complex and the acetyltransferase complex SAS, specifically promoting the acetylation of histone H4K16 in the region near telomeres and disrupting the telomeric heterochromatin structure to accelerate vascular EC senescence [64]. Lin et al. performed an overall lysine acetylome analysis in senescent HUVECs and found that 40 proteins associated with fatty acid metabolism had significantly reduced acetylation levels, thus also suggesting a relevance of EC senescence to acetylation [65]. SIRT is an NAD +dependent deacetylase [66]. ...
Endothelial cells, which are highly dynamic cells essential to the vascular network, play an indispensable role in maintaining the normal function of the body. Several lines of evidence indicate that the phenotype associated with senescent endothelial cells causes or promotes some neurological disorders. In this review, we first discuss the phenotypic changes associated with endothelial cell senescence; subsequently, we provide an overview of the molecular mechanisms of endothelial cell senescence and its relationship with neurological disorders. For refractory neurological diseases such as stroke and atherosclerosis, we intend to provide some valid clues and new directions for clinical treatment options.
... Наряду с этим, данные многочисленных экспериментальных работ демонстрируют такие свойства L-карнитина как антиоксидантный эффект [1,2,[8][9][10][11], возможность коррекции эндотелиальной дисфункции [8][9][10][11][12], влияние на процессы апоптоза и воспаления в различных тканях [11][12][13]. Механизмы описанных эффектов L-карнитина до настоящего времени остаются неясными. ...
... Наряду с этим, данные многочисленных экспериментальных работ демонстрируют такие свойства L-карнитина как антиоксидантный эффект [1,2,[8][9][10][11], возможность коррекции эндотелиальной дисфункции [8][9][10][11][12], влияние на процессы апоптоза и воспаления в различных тканях [11][12][13]. Механизмы описанных эффектов L-карнитина до настоящего времени остаются неясными. ...
... В этой связи представляется интересной концепция карнитинового гомеостаза S. ранее предложенная S. Sharma и соавторами, которая связывает содержание L-карнитина, его ацильных производных и активность карнитинпальмитоилтрансфераз с NO (II) опосредованной передачей сигналов и функцией митохондрий в клетках эндотелия легочной артерии [11]. Эта взаимосвязь подтверждается в более поздних работах связанных с эндотелиальной дисфункцией на фоне диабета, однако исследование этой связи в других органах остается малоизученным, что и стало целью текущей работы [10][11][12][13]. ...
Lipids are critical structural and functional architects of cellular homeostasis. Change in systemic lipid profile is a clinical indicator of underlying metabolic pathologies, and emerging evidence is now defining novel roles of lipids in modulating organismal ageing. Characteristic alterations in lipid metabolism correlate with age, and impaired systemic lipid profile can also accelerate the development of ageing phenotype. The present work provides a comprehensive review of the extent of lipids as regulators of the modern hallmarks of ageing viz., cellular senescence, chronic inflammation, gut dysbiosis, telomere attrition, genome instability, proteostasis and autophagy, epigenetic alterations, and stem cells dysfunctions. Current evidence on the modulation of each of these hallmarks has been discussed with emphasis on inherent age-dependent deficiencies in lipid metabolism as well as exogenous lipid changes. There appears to be sufficient evidence to consider impaired lipid metabolism as key driver of the ageing process although much of knowledge is yet fragmented. Considering dietary lipids, the type and quantity of lipids in the diet is a significant, but often overlooked determinant that governs the effects of lipids on ageing. Further research using integrative approaches amidst the known aging hallmarks is highly desirable for understanding the therapeutics of lipids associated with ageing.
Cell senescence denotes cell growth arrest in response to continuous replication or stresses damaging DNA or mitochondria. Mounting research suggests that cell senescence attributes to aging-associated failing organ function and diseases. Conversely, it participates in embryonic tissue maturation, wound healing, tissue regeneration, and tumor suppression. The acute or chronic properties and microenvironment may explain the double faces of senescence. Senescent cells display unique characteristics. In particular, its mitochondria become elongated with altered metabolomes and dynamics. Accordingly, mitochondria reform their function to produce more reactive oxygen species at the cost of low ATP production. Meanwhile, destructed mitochondrial unfolded protein responses further break the delicate proteostasis fostering mitochondrial dysfunction. Additionally, the release of mitochondrial damage-associated molecular patterns, mitochondrial Ca2+ overload, and altered NAD+ level intertwine other cellular organelle strengthening senescence. These findings further intrigue researchers to develop anti-senescence interventions. Applying mitochondrial-targeted antioxidants reduces cell senescence and mitigates aging by restoring mitochondrial function and attenuating oxidative stress. Metformin and caloric restriction also manifest senescent rescuing effects by increasing mitochondria efficiency and alleviating oxidative damage. On the other hand, Bcl2 family protein inhibitors eradicate senescent cells by inducing apoptosis to facilitate cancer chemotherapy. This review describes the different aspects of mitochondrial changes in senescence and highlights the recent progress of some anti-senescence strategies.
Endemic fluorosis is a global public health problem. Cardiovascular diseases caused by fluoride are closely related to endothelial cell injury. Metabolism disorder of endothelial cells (ECs) are recognized as the key factor of endothelial dysfunction which has been a hot topic in recent years. However, the toxic effect of fluoride on vascular endothelium has not been elucidated. The aim of this study was to explore the alteration of endothelial cell metabolites in Human Umbilical Vein Endothelial Cells (HUVECs) exposed to NaF using LC-MS/MS technique. The screening conditions were Variable Importance for the Projection (VIP) > 1 and P < 0.05. It was found that the expression of the metabolites Lumichrome and S-Methyl-5'-thioadenosine was upregulated and of the other metabolites, such as Creatine, L-Glutamate, Stearic acid was downregulated. Differential metabolites were found to be primarily related to FoxO、PI3K/Akt and apoptosis signaling pathways by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. From the perspective of metabolism, this study explored the possible mechanism of fluoride induced endothelial cell injury which providing theories and clues for subsequent studies.
