Incurable vascular diseases: New hope for treatment

Acetate regulates the endothelial-to-mesenchymal transition.

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Researchers have made a significant discovery in vascular diseases, uncovering a potential therapeutic option for previously incurable conditions. This breakthrough offers hope to individuals suffering from various vascular disorders, paving the way for innovative treatments that could improve patient outcomes and quality of life.

A new study led by Michael Simons, MD, reveals a groundbreaking discovery regarding the metabolic basis of vascular diseases and offers insights into their potential reversal. Once established, vascular diseases, such as atherosclerosis and pulmonary hypertension, have long been considered incurable and self-sustaining. However, the study sheds light on the endothelial-to-mesenchymal transition (EndMT) process, which perpetuates chronic inflammation in blood vessels.

The researchers identified an enzyme called ACSS2 as a critical player in this process. They demonstrated that inhibiting it significantly reduced the development of atherosclerosis in mice. The findings, published in Cell Metabolism, present a promising avenue for reversing previously incurable vascular diseases, providing hope for future therapeutic interventions.

Simons, who was the study’s co-principal investigator with Zoltan Arany, MD, Ph.D., Samuel Bellet Professor of Cardiology at the University of Pennsylvania’s Perelman School of Medicine, said, “We have a group of diseases that once started, they continue to go forward even if you remove the offending stimulus. We now uncovered the molecular basis of this persistence to understand why these diseases become stimulus-independent. We show that if we remove this underlying driver, we can reverse intractable illnesses and effectively treat people in ways that do not exist in the present.”

A new study led by Michael Simons, MD, reveals a groundbreaking discovery regarding the metabolic basis of vascular diseases and offers insights into their potential reversal. Once established, vascular diseases, such as atherosclerosis and pulmonary hypertension, have long been considered incurable and self-sustaining. However, the study sheds light on the endothelial-to-mesenchymal transition (EndMT) process, which perpetuates chronic inflammation in blood vessels.

The researchers identified an enzyme called ACSS2 as a critical player in this process. They demonstrated that inhibiting it significantly reduced the development of atherosclerosis in mice. The findings, published in Cell Metabolism, present a promising avenue for reversing previously incurable vascular diseases, providing hope for future therapeutic interventions.

Vascular abnormalities are critical in numerous chronic diseases, impacting organ function and overall health. Driven by the discovery of endothelial-to-mesenchymal transition (EndMT), which triggers chronic inflammation, Michael Simons, MD, and his team have been investigating the links between vascular abnormalities, disease, and aging. This process leads to abnormalities in endothelial cells, attracting inflammatory stimuli and resulting in the secretion of inflammatory cytokines.

Unfortunately, once initiated, the process becomes irreversible, making it challenging to treat chronic diseases associated with this chronic inflammatory process. The complexity lies in the unique signaling mechanism involved, where systemic agents would do more harm than good. Therefore, targeted therapies focusing on the endothelial cells are crucial for potential therapeutic interventions.

In a groundbreaking study, researchers have uncovered the metabolic basis of endothelial-to-mesenchymal transition (EndMT), a process implicated in chronic diseases. The team discovered that endothelial cells generally rely on sugar for energy and undergo extensive metabolic changes during EndMT. They found that TGF-β signaling induces the production of an excessive amount of acetyl-CoA (Ac-CoA), a molecule derived from acetate. Surprisingly, the acetate was generated by the endothelial cells themselves from sugar.

The team at Yale University began by exploring the metabolic changes that TGF-β signaling induced in endothelial cells and noticed that it led to the cells making an excessive amount of a molecule known as acetyl-CoA (Ac-CoA). Intrigued, the team looked for where the Ac-CoA came from. “And here there was a big surprise,” says Arany. “Much of the Ac-CoA came from acetate.”

The Ac-CoA played a crucial role in stabilizing TGF-β signaling and promoting the expression of TGF-β receptors, making the endothelial cells susceptible to the harmful effects of TGF-β. The team also identified the enzyme ACSS2 as essential for Ac-CoA synthesis in endothelial cells. In mouse models of atherosclerosis, deleting the ACSS2 gene significantly reduced the development of the disease. These findings offer promising avenues for developing novel therapeutic strategies targeting EndMT and potentially improving patient outcomes in chronic diseases.

In conclusion, this study has unveiled the crucial role of acetate in controlling endothelial-to-mesenchymal transition (EndMT). The findings highlight how metabolic changes in endothelial cells lead to acetyl-CoA (Ac-CoA) production from acetate, stabilizing TGF-β signaling and promoting the expression of TGF-β receptors. The team’s experiments, including the deletion of the ACSS2 gene in mouse models of atherosclerosis, have demonstrated the potential therapeutic implications of targeting this pathway. These insights into the metabolic basis of EndMT pave the way for developing innovative treatments for chronic diseases associated with this process, offering new hope for patients in the future.

Journal Reference:

  1. Xiaolong Zhu Yunyun Wang et al. Acetate controls endothelial-to-mesenchymal transition. Cell Metabolism. DOI:10.1016/j.cmet.2023.05.010
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