Publications by authors named "Astrid Rodriguez-Velez"

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects.

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Background: The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages.

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Article Synopsis
  • White adipose tissue (WAT) transplantation is used in research to study the role of fat cells and associated immune cells in metabolism.* -
  • Mice are typically used as models for this type of transplant, moving fat from a donor to either a similar site on the same mouse or to another mouse.* -
  • The article outlines the heterologous fat transplantation procedure, including necessary surgical care and how to confirm the success of the graft through histology.*
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Previous studies have demonstrated that a high-protein diet leads to increased atherosclerosis in mice, and that this adverse effect is caused by activation of macrophage mTORC1 signaling. Here, we provide a detailed protocol for the evaluation of diet-induced mTORC1 signaling in plaque macrophages in atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice. This protocol includes flow cytometry and immunofluorescence analysis of atherosclerotic macrophages that can be used to study the atherogenic potential of a variety of mTORC1 modulators.

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Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles.

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The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system.

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Introduction: Inflammasomes are central to atherosclerotic vascular dysfunction with regulatory effects on inflammation, immune modulation, and lipid metabolism. The NLRP3 inflammasome is a critical catalyst for atherogenesis thus highlighting its importance in understanding the pathophysiology of atherosclerosis and for the identification of novel therapeutic targets and biomarkers for the treatment of cardiovascular disease.

Areas Covered: This review includes an overview of macrophage lipid metabolism and the role of NLRP3 inflammasome activity in cardiovascular inflammation and atherosclerosis.

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High protein diets are commonly utilized for weight loss, yet have been reported to raise cardiovascular risk. The mechanisms underlying this risk are unknown. Here, we show that dietary protein drives atherosclerosis and lesion complexity.

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p62/ is a multifunctional scaffolding protein involved in the regulation of various signaling pathways as well as autophagy. In particular, p62/SQSTM1 serves as an essential adaptor to identify and deliver specific organelles and protein aggregates to autophagosomes for degradation, a process known as selective autophagy. With the emergence of autophagy as a critical process in cellular metabolism and the development of cardiometabolic diseases, it is increasingly important to understand p62's role in the integration of signaling and autophagic pathways.

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