In this issue of Acta Physiologica, Heuschkel et al. Present compelling evidence of the hypotaurine metabolic pathway being involved in glucose-induced vascular smooth muscle cell (SMC) calcification. Using state-of-the-art in vitro approaches, their study reveals that elevated glucose levels in SMCs promote extracellular matrix calcification, suggesting potential novel therapeutic targets for hyperglycemia-driven vascular disease [1].
With the global rise in type 2 diabetes (T2D) and accompanying macrovascular complications, manifestations of atherosclerosis and arterial stiffening pose major clinical challenges. Vessels of diabetic patients present increased intimal and medial calcification, which has been associated with cardiovascular events and poor outcomes [2]. It has been hypothesized that prevention or halted calcification can improve clinical outcomes in diabetic populations.
Vascular calcification is an active process that involves many factors such as metabolic changes, oxidative stress, inflammation, and cellular trans-differentiation. In individuals with T2D, chronic hyperglycemia accelerates this process by promoting the production of advanced glycosylation end-products, endothelial dysfunction and immune cell infiltration, creating a microenvironment that favors the osteochondrogenic transformation of SMCs within the vessel wall [3]. However, despite decades of research, no pharmacological therapy has been approved to prevent or reverse vascular calcification. One major challenge lies in the overlap between many of the key molecular pathways involved in vascular calcification and those in bone metabolism, posing difficulties in targeting either of them without systemic side effects. Furthermore, the vast complexity of calcification, including different types such as macro- and micro-calcification, different stages during the progression of calcification formation, and the fact that it is usually detected at an advanced irreversible stage, all indicate that it cannot be targeted uniformly. To date, no safe, specific, and effective pharmacological treatment has been validated in clinical trials, underscoring an urgent need for novel research strategies and targets in this field.
In this study, Heuschkel et al. investigate the SMC-related metabolic changes that result in calcification under hyperglycemic conditions. In the search for novel pathways and targets, they employ a multi-omics approach integrating transcriptomic and metabolomic data derived from in vitro glucose-induced calcifying SMCs. As expected, high glucose promoted calcification of SMCs. However, this was not accompanied by the upregulation of classical osteochondrogenic markers such as ALPL, RUNX2, BMP2, and SOX9, suggesting the involvement of alternative mechanisms. Through integrated analysis of transcriptomic and intra- and extra-cellular metabolomic data, the authors identified the hypotaurine met
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