Endothelial decorin is increased by ageing and, induces inflammation and diastolic dysfunction in the heart

Abstract

AimsCardiovascular disease is the leading cause of death in the European Union and aging is one of its major risk factors resulting in the progressive deterioration of the cardiac structures and function. Here, we have combined single-nucleus-RNA-sequencing, imaging, and molecular and cell biology approaches to explore the maladaptive signals that drive cardiac ageing. Methods and resultsSingle-nucleus-RNA-sequencing analysis of young (3 months) and old (18 months) murine hearts revealed that the expression of decorin, a secreted proteoglycan expressed in the extracellular matrix of endothelial cells, is induced by ageing. Decorin treatment via osmotic mini-pump induced diastolic dysfunction and a pro-inflammatory environment in the myocardium characterized by increased infiltration of immune cells, increased expression of IL- 1{beta} in endothelial cells and microvascular leakage in 3 months old mice. In vitro, decorin treatment induces cardiomyocyte hypertrophy, the expression of different pro-inflammatory cytokines like IL1B in endothelial cells, and compromises the endothelial barrier function. ConclusionsTogether, our results identify decorin as a novel player contributing to cardiac aging and disease. Decorin contributes to the age-related structural and functional dysfunction of the heart by inducing a pro-inflammatory environment in the myocardial microvasculature, a hallmark of cardiac ageing. Translational perspectiveAgeing is a major risk factor of cardiovascular disease and the molecular and cellular mechanisms that drive this process have not been completely described. The data presented here identifies decorin as a novel player contributing to systemic inflammation and microvascular dysfunction, two hallmarks of ageing. Although, because of its role regulating TGF-{beta} signalling, decorin has been proposed for anti-fibrotic therapies, the pro-inflammatory effects observed on the cardiac microvasculature should be taken into account for the employment of decorin as an antifibrotic agent to treat disease associated cardiac fibrosis.