Abstract
We previously reported heightened expression of the human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages of patients with PA hypertension (PAH). Furthermore, recombinant HERV-K dUTPase increased IL-6 in PA endothelial cells (PAECs) and caused pulmonary hypertension in rats. Here we show that monocytes overexpressing HERV-K dUTPase, as opposed to GFP, can release HERV-K dUTPase in extracellular vesicles (EVs) that cause pulmonary hypertension in mice in association with endothelial mesenchymal transition (EndMT) related to induction of SNAIL/SLUG and proinflammatory molecules IL-6 as well as VCAM1. In PAECs, HERV-K dUTPase requires TLR4-myeloid differentiation primary response–88 to increase IL-6 and SNAIL/SLUG, and HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) is necessary to upregulate VCAM1. TLR4 engagement induces p-p38 activation of NF-κB in addition to p-pSMAD3 required for SNAIL and pSTAT1 for IL-6. HERV-K dUTPase interaction with MCAM also induces p-p38 activation of NF-κB in addition to pERK1/2-activating transcription factor-2 (ATF2) to increase VCAM1. Thus in PAH, monocytes or macrophages can release HERV-K dUTPase in EVs, and HERV-K dUTPase can engage dual receptors and signaling pathways to subvert PAEC transcriptional machinery to induce EndMT and associated proinflammatory molecules.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by obstructive intimal and plexiform lesions in small pulmonary arteries (PAs) that cause increased resistance to flow
We investigated whether Human endogenous retrovirus (HERV)-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can induce endothelial mesenchymal transition (EndMT), a feature increasingly linked to the structural remodeling of PA hypertension (PAH) [3, 4, 18]
We showed that HERV-K induces initial apoptosis in PA endothelial cells (PAECs) followed by resistance to apoptosis, a feature of EndMT (Supplemental Figure 1B)
Summary
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by obstructive intimal and plexiform lesions in small pulmonary arteries (PAs) that cause increased resistance to flow. The proliferative expansion of dedifferentiated smooth muscle cells (SMCs) causing the obstructive neointima is, at least in part, the consequence of pulmonary arterial endothelial cell (PAEC) dysfunction. Many factors can contribute to EndMT, including loss of function of bone morphogenetic protein receptor-2 (BMPR2), a gene that is mutated in most patients with familial PAH and in 20% of those without a family history of PAH [6]. Viruses such as CoxsackieB3 have been implicated in EndMT in the heart [7]
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