Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction.

Aims: Microvascular dysfunction has been proposed to drive heart failure with preserved ejection fraction (HFpEF), but the initiating molecular and cellular events are largely unknown. Our objective was to determine when microvascular alterations in HFpEF begin, how they contribute to disease progression, and how pericyte dysfunction plays a role herein.

Methods And Results: Microvascular dysfunction, characterized by inflammatory activation, loss of junctional barrier function, and altered pericyte-endothelial crosstalk, was assessed with respect to the development of cardiac dysfunction, in the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at three time points: 6, 14, and 21 weeks of age.

Spatial Mechano-Signaling Regulation of GTPases through Non-Degradative Ubiquitination.

Blood flow produces shear stress exerted on the endothelial layer of the vessels. Spatial characterization of the endothelial proteome is required to uncover the mechanisms of endothelial activation by shear stress, as blood flow varies in the vasculature. An integrative ubiquitinome and proteome analysis of shear-stressed endothelial cells demonstrated that the non-degradative ubiquitination of several GTPases is regulated by mechano-signaling.

Neutrophil peptidylarginine deiminase 4 is essential for detrimental age-related cardiac remodelling and dysfunction in mice.

Mice fully deficient in peptidylarginine deiminase 4 (PAD4) enzyme have preserved cardiac function and reduced collagen deposition during ageing. The cellular source of PAD4 is hypothesized to be neutrophils, likely due to PAD4's involvement in neutrophil extracellular trap release. We investigated haematopoietic PAD4 impact on myocardial remodelling and systemic inflammation in cardiac ageing by generating mice with deletion in circulating neutrophils under the MRP8 promoter (Ne-PAD4), and ageing them for 2 years together with littermate controls (PAD4).

AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis.

Viral myocarditis (VM) is an important cause of heart failure (HF) in children and adults. However, the molecular determinants involved in cardiac inflammation and cardiomyocyte necrosis remain poorly characterized, and cardioprotective molecules are currently missing. Here, we applied an in vivo method based on the functional selection (FunSel) of cardioprotective factors using AAV vectors for the unbiased identification of novel immunomodulatory molecules in a Coxsackievirus B3 (CVB3)-induced myocarditis mouse model.

Neutrophil inhibition improves acute inflammation in a murine model of viral myocarditis.

Aims: Viral myocarditis (VM) is an inflammatory pathology of the myocardium triggered by a viral infection that may cause sudden death or heart failure (HF), especially in the younger population. Current treatments only stabilize and improve cardiac function without resolving the underlying inflammatory cause. The factors that induce VM to progress to HF are still uncertain, but neutrophils have been increasingly associated with the negative evolution of cardiac pathologies.