Acta Physiologica最新文献

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

Sodium (Na⁺) supports metabolic, neural, and muscular functions, and plays a critical role in fluid volume and blood pressure homeostasis. For many wild mammals, inadequate Na⁺ intake can lead to hyponatremia, where low Na⁺ levels disrupt fluid balance and may cause seizures or death [1]. Conversely, chronic excess in Na⁺ intake, common in both humans and domestic animals, may increase blood pressure and elevate the risk of cardiovascular disease and premature death [2]. Nevertheless, there remains considerable debate regarding the mechanisms of Na⁺ balance and why some individuals exhibit greater Na⁺ sensitivity [3].

Mammals, including humans, assimilate most (> 90%) of their dietary Na⁺ into the bloodstream [4]. Consequently, elevated Na⁺ consumption can quickly raise blood Na⁺ levels above the narrow limits required to maintain osmotic balance and blood pressure. To prevent this, mammals have evolved a number of mechanisms for regulating excess Na⁺ from the body [4]. The primary pathway is renal excretion of Na⁺ in urine [1, 3]. A secondary mechanism involves secretion of Na⁺ from the bloodstream into the large intestine for elimination in feces, though this is typically an order of magnitude smaller [4]. Third, mammals have evolved a specialized mechanism for buffering excess Na⁺ in the bloodstream: the temporary storage of Na⁺ in extrarenal body tissues [5].

The idea that mammals can store excess Na⁺ originated in the early 1900s, but more contemporary work by Titze and colleagues has shifted the paradigm regarding how the body handles excess Na [5, 6]. Traditionally, it was believed that increased Na⁺ intake required proportional increases in water to maintain extracellular osmolarity, while the kidneys excreted surplus Na⁺ to restore Na⁺ balance. However, recent evidence suggests that Na⁺ can be stored in extrarenal body tissues without commensurate water retention [5]. Most research has identified skin and muscle as the primary sites of Na storage, where Na⁺ binds to negatively charged glycosaminoglycans (GAGs) [5]. However, bone contains ~45% of total body Na, and while only one third of this Na⁺ is thought to be readily exchangeable [3], this would represent a substantial component of the body's short-term Na storage capacity. Still, the magnitude and dynamics of extrarenal Na⁺ storage remain poorly understood, with inconsistencies among species and individuals. For example, a study on dogs showed no signs of extrarenal Na⁺ storage [7], while others suggested that Na⁺ associated with GAGs remai