Abstract 18787: Overexpression of TCTP/TPT1 Markedly Enhances Selective Export in Exosomes From Apoptotic Endothelial Cells, Mediating Smooth Muscle Cell Growth Dysregulation

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Abstract

Background: Recent studies have shown that endothelial cell (EC) apoptosis is a central trigger for pulmonary arterial hypertension (PAH), resulting in the emergence of growth-dysregulated and apoptosis-resistant vascular cells that contribute to the formation of complex neoplastic-like vascular lesions. However, the mechanism which links EC apoptosis to dysregulated growth is not yet known. Our lab has identified increased expression of translationally controlled tumor protein (TCTP/TPT1), a protein implicated in transformation of neoplastic cells in cancer, in blood outgrowth ECs from patients with PAH. Moreover, TCTP expression was detected in obliterative intimal lesions of an experimental rat model of severe PAH that was induced by a treatment with a VEGFR2 antagonist SU5416, and found to be elevated in the lungs of patients with PAH; tightly localized to complex arterial lesions.

Hypothesis: TCTP represents a molecular link between EC injury and apoptosis and the subsequent emergence of growth dysregulated cells, contributing to the development of plexiform lesions in PAH.

Methods and Results: Human umbilical vein endothelial cells (HUVEC) and pulmonary artery smooth muscle cells (PASMC) were transduced with a lentivirus vector containing human or rat TCTP sequence. Compared to non-transduced or null transduced cells, TCTP overexpression led to increases in BrdU incorporation and cell number, associated with significant reductions in caspase activity in serum-starved ECs and SMCs. As well, overexpression of TCTP markedly increased its secretion from apoptotic ECs, largely in the exosome fraction of the conditioned media (CM). In contrast, despite similar levels of overexpression, no export of TCTP was observed by apoptotic SMCs. Moreover, while apoptotic EC-CM significantly increased proliferation and inhibited apoptosis in SMCs, it had no effect on growth and survival of ECs.

Conclusions: These findings suggest that TCTP is specifically released in exosomes from apoptotic ECs and mediates unidirectional EC to SMC signaling that promotes a growth-dysregulated phenotype. TCTP may contribute to the formation of complex lung arterial lesions, leading to arteriolar remodeling in PAH and represents a potential therapeutic target.

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