PTX3 enhances inflammation and fibrosis in vascular smooth muscle cells with BMPR2 dysfunction, and PTX3 antibody reverses these effects in PAH models (p<0.05).
Does PTX3 exacerbate inflammation and fibrosis in vascular smooth muscle cells with BMPR2 dysfunction?
PTX3 enhances inflammation and fibrosis in vascular smooth muscle cells under BMPR2 dysfunction, highlighting its potential as a therapeutic target in pulmonary arterial hypertension.
Absolute Event Rate: 0% vs 0%
Abstract Background Pulmonary arterial hypertension (PAH) is a rare chronic cardiovascular disease characterized by increased pulmonary vascular resistance, vascular remodeling, and right ventricle failure, often leading to mortality. While its mechanisms remain unclear, PAH is linked to genetic mutations, inflammation, and hypoxia. BMPR2 mutation, the most common genetic cause of PAH, drives vascular remodeling by inducing abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Inflammation accelerates PAH progression as cytokines like as IL-6, IL-1β, and TNFα enhance cell proliferation, migration and extracellular matrix (ECM) deposition, contributing to fibrosis and vessel wall thickening. Pentraxin 3 (PTX3), a pro-inflammatory protein secreted by endothelial cells, fibroblasts, and macrophages, activates inflammatory and fibrotic pathways via CD44. Elevated PTX3 levels in PAH patients and models suggest its therapeutic potential, as targeting PTX3 alleviates vascular fibrosis, inflammatory responses, and right ventricular hypertrophy. Hypothesis PTX3 exacerbates inflammation and fibrosis in PAH characterized by BMPR2 dysfunction. Experimental design and Results In this study, we used small interfering RNA targeting BMPR2 (siBMPR2) to induce BMPR2 dysfunction in VSMCs. According to the results, cell proliferation, migration, and IL-6 expression were all markedly increased after 12 hr of effective inhibition of BMPR2 expression. Additionally, BMPR2-knockdown VSMCs indirectly stimulated the expression of PTX3 and CD44 proteins in fibroblasts. Subsequently, VSMCs were treated with PTX3 alone, and it was found that PTX3 promoted the expression of fibronectin (FN) but didn’t significantly induce cell proliferation or IL-6 protein level (FN: control vs. PTX3 = 0.49-folded vs. 1.05-folded, p0.01; cell proliferation: control vs. PTX3 = 104% vs. 102.6%, p0.05; IL-6: control vs. PTX3 = 0.3-folded vs. 0.28-folded, p0.05). Finally, siBMPR2 and PTX3 were used in combination to stimulate VSMCs, and PTX3 antibodies were applied to neutralize its effects, in order to validate the role of PTX3 in BMPR2 dysfunction. Our results showed that dual stimulation exacerbated the expression of fibrosis-related proteins and inflammatory factors (control vs. siBMPR2+PTX3, p0.05). However, treatment with PTX3 antibodies (PTX3 ab) effectively reversed these fibrosis and inflammation in VSMCs (siBMPR2+PTX3 vs.PTX3 Ab, p0.05). Conclusion Our findings indicate that PTX3 enhances inflammation and fibrosis in VSMCs under condition of BMPR2 dysfunction, highlighting its critical role in PAH progression and potential as a therapeutic target.Proposed PTX3-BMPR2 in PAH mechanism
Liu et al. (Sat,) reported a other. PTX3 enhances inflammation and fibrosis in vascular smooth muscle cells with BMPR2 dysfunction, and PTX3 antibody reverses these effects in PAH models (p<0.05).