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Pericardial Fluid of Patients with Coronary Artery Disease Can Drive Fibrosis via TGF-Beta Signalling Pathway

ABSTRACT: Pericardial fluid (PF) helps maintain homeostatic conditions that facilitate optimal heart function. We have yet to understand how cardiovascular pathologies affect the profile of PF. We hypothesized that human PF contains immune markers that can be affected by different pathologies and contribute to inflammatory-mediated processes, such as fibrosis. PF was collected from patients undergoing cardiac surgery. Multiplex analysis was performed to determine the composition of inflammatory markers and soluble mediators. A gel contraction assay was used to investigate the fibrotic potential of PF. RNA-sequencing was used to elucidate the mechanisms driving the pro-fibrotic properties of PF. With the results of these multiple approaches we show that the acellular component of PF has pro-fibrotic characteristics and suggest putative mechanisms that can explain such observations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262161 | GEO | 2024/12/06

REPOSITORIES: GEO

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Project description:Aims: In humans, secretome of pericardial (PAT) and epicardial adipose tissue (EAT) contribute to establishment of heart failure (HF) with preserved ejection fraction (HFpEF) originating from pressure-overload due to metabolic disorder. We examined whether PAT affects also manifestation and progression of pressure-induced HF in the absence of metabolic burden in mice. Methods and results: Progressive remodelling was assessed in C57BL/6J males, aged 9 wks, randomly assigned to sham surgery or transverse aortic constriction (TAC) for 1 week (early pressure-overload), 8 (chronic pressure-overload), or 12 weeks (HFrEF) with or without concomitant PAT excision. PAT removal did not affect early (1 wk TAC), and chronic (8 wks) pressure-overload induced concentric remodelling. However, the initial PAT excision prevented TAC-induced expansion of pro-inflammatory macrophages during early pressure-overload and attenuated the persistent LV expression of pro-hypertrophic, pro-inflammatory and pro-fibrotic factors as well as the drastic LV dilation and progressive systolic dysfunction in the long-term and thereby protected against the transition to HFrEF. This protection was associated with significant reduction of microscar and perivascular fibrosis. The latter was, at least in part, attributed to reduced accumulation of pro-fibrotic CD206+ macrophages around the coronaries 12 wks post-surgery in the absence of PAT compared to mice with intact PAT. In addition, PAT bulk RNA sequencing revealed the initiation of an extracellular matrix deposition programme in the PAT early upon TAC surgery, which might trigger fibrotic responses in the underlying myocardium. Indeed, isolated naive adult cardiac fibroblasts exposed to PAT lysate from 12 wks TAC mice increased collagen production and cell viability/proliferation. Conclusion: Our data suggest PAT to play divergent roles in the chronically pressure overloaded heart versus HFrEF - while widely not affecting concentric hypertrophy, PAT removal counteracts manifestation of HFrEF in mice, at least in part, by preventing excessive fibrotic and macrophage responses.

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Pericardial Fluid of Patients with Coronary Artery Disease Can Drive Fibrosis via TGF-Beta Signalling Pathway

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