Dietary Intake and Glutamine-Serine Metabolism Control Pathologic Vascular Stiffness

Medicine Respiratory System Cell Biology Bioengineering Biochemistry Cardiovascular System Life Sciences Immunology
dietary intake glutamine metabolism serine metabolism vascular stiffness pulmonary hypertension cardiovascular diseases

Research Background

Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide, with vascular remodeling and stiffness being critical indicators that significantly affect disease progression and prognosis. Recent studies have increasingly focused on the role of vascular fibroblasts in vascular stiffness and remodeling. In particular, understanding the metabolic pathways of vascular fibroblasts is crucial for developing new therapeutic approaches to combat pulmonary hypertension (PH), a fatal pulmonary vascular disease.

Source of the Paper

The study titled “Dietary Intake and Glutamine-Serine Metabolism Control Pathologic Vascular Stiffness” was conducted by Nesrine S. Rachedi, Ying Tang, and many other authors. It was a collaboration involving several institutions, including Université Côte d’Azur, CNRS, INSERM, IHU-RESPIRE in France, and the University of Pennsylvania School of Medicine in the United States. The paper was published in the journal Cell Metabolism on June 4, 2024.

Research Objective

The study aims to elucidate how vascular fibroblasts maintain collagen biosynthesis through reprogramming their metabolic pathways in pulmonary hypertension, ultimately leading to pathological vascular stiffness. Using a series of metabolic discovery platforms, including in vitro cell models, in vivo mouse models, and lung tissue from PH patients, the research team sought to clarify the specific metabolic requirements of fibroblasts during pathological activation. This understanding is essential for developing drugs or dietary interventions targeting these metabolic pathways to reduce collagen production and improve vascular function.

Research Workflow

The research was conducted through a series of experimental procedures:

  1. Cell Culture and Activation:

    • Pulmonary arterial adventitial fibroblasts (PAAFs) were cultured on substrates of varying stiffness and exposed to pulmonary hypertension triggers such as hypoxia and inflammatory factors.
    • Metabolomics analyses were used to examine the metabolic state changes in PAF cells under these conditions, determining whether they increased glutamine and serine uptake to maintain collagen biosynthesis.

  2. Metabolic Pathway Analysis:

    • Stable isotope tracing techniques (e.g., [U-13C]-glucose, [U-13C]-glutamine) were employed to trace different carbon sources’ metabolic pathways within the cells, particularly how glutamine and serine are converted into proline and glycine to support collagen production.
    • PET imaging technology using 18F-labeled fluoro-glutamine (18F-FGln) was utilized to display glutamine uptake in the lungs and pulmonary vasculature.

  3. Genetic Intervention Experiments:

    • Small interfering RNA (siRNA) and small molecule inhibitors were used to intervene in the expression of glutaminase (GLS1) and serine hydroxymethyltransferase (SHMT1) to observe the effect of inhibiting these two enzymes on collagen synthesis.
    • Gene chip and qPCR experiments were conducted to determine the regulatory role of YAP/TAZ transcription factors in the glutamine and serine metabolic pathways.

Main Research Results

  1. Activation and Metabolic Reprogramming of Fibroblasts:

    • The study showed that activated PAAFs significantly increased their uptake of glutamine and serine to produce proline and glycine, thereby promoting collagen synthesis and vascular stiffness.
    • Metabolic pathway analysis confirmed that the metabolic reprogramming of fibroblasts involved upregulation of multiple genes related to collagen metabolism.

  2. Genetic Intervention and Metabolic Inhibition:

    • Knockdown of GLS1 or SHMT1 via siRNA, as well as simultaneous knockdown of both genes, resulted in a significant decrease in proline and glycine production in activated fibroblasts, reducing collagen synthesis.
    • In drug intervention experiments, the combined use of GLS1 and SHMT1 inhibitors, CB-839 and SHIN1, showed superior performance in reducing pulmonary arterial stiffness and improving various pathological indicators of pulmonary hypertension compared to single drug use.

  3. Regulatory Role of YAP/TAZ:

    • Experiments indicated that YAP and TAZ coordinate collagen biosynthesis and metabolic demand by regulating the expression of multiple genes. These genes include key enzymes involved in the conversion of glutamine and serine to proline and glycine pathways.

  4. Dietary Intervention Improving Pathological Vascular Stiffness:

    • Restricting dietary intake of glutamine and serine significantly reduced the plasma levels of these amino acids in rats, decreased collagen content in pulmonary vessels, and alleviated the pathological manifestations of vascular stiffness and pulmonary hypertension.

Research Conclusion

This study clarifies the metabolic requirements of glutamine and serine in pathological vascular stiffness and their critical role in collagen biosynthesis. It provides new ideas for drug and dietary interventions targeting these metabolic pathways. The YAP and TAZ transcription factors, as central regulators of this metabolic reprogramming, warrant further exploration in the context of metabolic diseases and cancer.

Research Highlights

  • Identification of Metabolic Pathways: This study is the first to clearly define the importance of glutamine and serine metabolism in collagen synthesis.
  • YAP/TAZ Regulation: It reveals that YAP and TAZ influence collagen biosynthesis and vascular stiffness by regulating glutamine and serine metabolic pathways.
  • Therapeutic Innovation: It proposes a new strategy to control pathological vascular stiffness through metabolic and dietary intervention, providing new insights and potential treatment approaches for cardiovascular diseases, particularly pulmonary hypertension.

Scientific and Applied Value of the Research

This study expands our understanding of the metabolic needs of pathological activation of fibroblasts in cardiovascular diseases and provides scientific evidence for the development of novel drug and dietary interventions. The in-depth exploration of dietary intervention holds great potential for preventing and treating cardiovascular diseases. Additionally, the key role of YAP/TAZ in regulating cellular metabolic reprogramming offers important clues for research on other metabolic-related diseases.

Additional Valuable Information

  • Potential of Non-Invasive Imaging Technologies: The PET imaging technology based on the findings of this study holds promise for early diagnosis and monitoring of the progression of pulmonary hypertension and other cardiovascular diseases.
  • Broader Application Prospects: The metabolic reprogramming of glutamine and serine may have universal implications in various fibrotic diseases, providing important insights for exploring treatment strategies for these conditions.

This study advances our understanding of the pathological mechanisms of cardiovascular diseases in several ways and provides a solid scientific basis for future therapeutic strategies.