Cardiac ageing is associated with progressive structural and functional remodelling, involving both cellular and extracellular compartments. Hallmarks include fibrosis, cardiomyocyte hypertrophy, chronic low-grade inflammation, and microvascular dysfunction, all of which contribute significantly to the development of cardiac dysfunction [1]. As the global population continues to age, elucidating the molecular mechanisms that drive these pathological changes has become a pressing unmet clinical need.

One well-established feature of cardiac ageing is the alterations of the extracellular matrix (ECM), which contribute to myocardial stiffening and impaired diastolic function [2]. In this context, the study by Luxán et al. [3] provides compelling evidence that decorin, a small leucine-rich proteoglycan, may be a novel contributor to age-related cardiac inflammation and microvascular dysfunction.

Using single-nucleus transcriptomics comparing young and aged mice, the authors identified significant dysregulation of ECM-related genes. Among these, decorin emerged as a candidate of interest, as it accumulated in aged hearts, specifically in its non-glycated form. To investigate causality, young mice were treated with exogenous decorin via osmotic minipumps. Strikingly, decorin administration induced diastolic dysfunction and a pro-inflammatory myocardial environment, characterized by immune cell infiltration, increased IL-1β expression in endothelial cells, and microvascular leakage, all occurring in the absence of fibrosis. Interestingly, these characteristics of diastolic dysfunction and low grade inflammation resembles that observed in the aged heart and in early heart failure with preserved ejection fraction (HFpEF), particularly its inflammatory-obese phenotype.

Detailed microvascular analysis revealed capillary enlargement without changes in vascular density, a feature previously reported in aged murine hearts. Moreover, plasma albumin extravasation into the myocardium confirmed compromised vascular integrity. Furthermore, in vitro assays using human microvascular endothelial cells confirmed that decorin directly impairs endothelial barrier function.

Mechanistically, decorin was shown to act directly on endothelial cells, triggering a robust pro-inflammatory cytokine response. These findings support the role of decorin as a damage-associated molecular pattern (DAMP) that engages Toll-like receptor 2 to promote endothelial inflammation [4], a mechanism that may underlie broader aspects of cardiac dysfunction during ageing.

Paradoxically, no cardiac fibrosis, defined as excessive collagen fibres deposition, was observed in this model. This may relate to decorin’s known ability to interfere with TGF-β-mediated signalling [5]. These findings underscore the importance of ECM alterations beyond mere collagen accumulation, highlighting that not only the quantity but also the organization and composition of the ECM critically influence its impact on cardiac remodelling.

In conclusion, this study identifies endothelial cells as key targets of decorin-driven inflammation and offers novel insight into the complex interplay between ECM remodelling, vascular function, and inflammation in the ageing heart. Whether targeting the decorin-TLR2 axis can mitigate age-related cardiovascular dysfunction remains an exciting avenue for future investigation.