PTX3 Predicts Myocardial Damage and Fibrosis in Duchenne Muscular Dystrophy

Abstract

Pentraxin 3 (PTX3) is a main component of the innate immune system by inducing complement pathway activation, acting as an inflammatory mediator, coordinating the functions of macrophages/dendritic cells and promoting apoptosis/necrosis. Additionally, it has been found in fibrotic regions co-localizing with collagen. In this work, we wanted to investigate the predictive role of PTX3 in myocardial damage and fibrosis of Duchenne muscular dystrophy (DMD). DMD is an X-linked recessive disease caused by mutations of the dystrophin gene that affects muscular functions and strength and accompanying dilated cardiomyopathy. Here, we expound the correlation of PTX3 cardiac expression with age and Toll-like receptors (TLRs)/interleukin-1 receptor (IL-1R)-MyD88 inflammatory markers and its modulation by the so-called alarmins IL-33, high-mobility group box 1 (HMGB1), and S100β. These findings suggest that cardiac levels of PTX3 might have prognostic value and potential in guiding therapy for DMD cardiomyopathy.

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

“…Natural Killer (NK) cells and monocytes are linked through a feed-forward amplification loop of T-bet/IFN-/IL-12 signalling, which causes the mutual activation of both NK cells and monocytes and fosters the recruitment of inflammatory cells to sites of inflammation [28]. Tregs coordinate M1 and M2 macrophage activation [29]: as described in detail in the 3.3.…”

Short‐term tetrabromobisphenol A exposure promotes fibrosis of human uterine fibroid cells in a 3D culture system through TGF‐beta signaling

“…This implied the activation of typical TGFB/SMAD signaling. The activated phosphorylation residues for SMADs were SMAD2/3 (Thr‐8), SMAD3 (Ser204), and SMAD3 (Thr179) (Figure S3d), which have been reported to be associated with hepatic fibrogenesis or myocardial fibrosis 30,31 …”

“…The activated phosphorylation residues for SMADs were SMAD2/3 (Thr-8), SMAD3 (Ser204), and SMAD3 (Thr179) (Figure S3d), which have been reported to be associated with hepatic fibrogenesis or myocardial fibrosis. 30,31 Further function analysis of the three combined networks of protein expression data was conducted to investigate their association with fibrosis. There were 10 proteins associated with fibrogenesis, eight of which have red relationship lines predicted the activation of fibrogenesis, including the TGFB1 ligand and its receptors, TGFBR1 and TGFBR2, as well as MAP2K6, MAPK8, CFL1, SMAD2, and SMAD3 as downstream molecules (Figure 7).…”

Flavonoids and Omega3 Prevent Muscle and Cardiac Damage in Duchenne Muscular Dystrophy Animal Model

“…One possible mechanism through which MMP-9 may blunt cardiac inflammation could be by reducing S100-β alarmin and PTX3 protein levels. In FLAVOmega β treated muscles, we observed a low expression of TNF-α and pSMAD2-3 and the downregulation of S100-β alarmin and PTX3 expression, usually highly expressed in dystrophic cardiomyopathy [ 26 ], in 3-month-old mdx mice treated with FLAVOmega β (S100-β: p = 0.0214; PTX3: p = 0.0222) compared to age-matched mdx control ( Figure 8 B). All these data suggest an anti-inflammatory effect of FLAVOmega β in dystrophic cardiac remodeling.…”

“…These cardiometabolic benefits might be related to improved endothelial production of eNOS, as observed in skeletal muscle [ 44 ], and to a modulation of PTX3-related pathways, which are known to be predictive of myocardial damage and fibrosis in mdx mice. However, due to its late onset (starting from 8 month of age), the effective role of FLAVOmega β in the modulation of the dilated cardiomyopathy phenotype is yet to be established via additional in vivo studies on older mice [ 26 ].…”