Abstract 1707: Murine γHerpesvirus-68 Infection Induces Pulmonary Vascular Disease in S100A4 Overexpressing Mice Associated with Elastase Activity and Altered MicroRNA Expression
Human γ herpesvirus infection is linked to idiopathic pulmonary arterial hypertension (IPAH). S100A4, a metastasis gene, is highly expressed in the plexiform lesions of IPAH patients. Previously, we reported that murine γherpesvirus-68 (M1-MHV-68) infection in S100A4 overexpressing but not in C57 wild-type (WT) mice induced mild neointimal formation in pulmonary arteries (PA) associated with heightened serine elastase activity. We hypothesized that these neointimal lesions would progress during an extended reactivation phase, in the S100A4 mice in association with ongoing elastolysis and that the susceptibility in S100A4 mice was related either to viral load, inflammation or differential induction of host miRNAs in response to infection. We now report that the % of vessels with neointimal lesions progressively increased from 25 to 40%, between 3 and 6 mo after viral infection (P < 0.05) in S100A mice but were not observed in WT. The extent of neointimal lesions correlated with progressive fragmentation of the elastic laminae, (P < 0.001). Interestingly, these features were not sufficient to induce elevated RVSP or RVH, in the absence of muscularization or loss of distal PAs. Susceptibilty of S100A4 mice was not related to an increase in viral DNA in intra-pulmonary arteries assessed by laser capture microscopy, nor could we establish a relationship with the severity of perivascular inflammation or cytokine expression (IFN-γ and TNF-α). However, we confirmed higher lung serine elastase activity in S100A4 vs. C57 mice as early as 1 wk after viral infection. Since expression of miRNAs may be responsible for host susceptibility, we compared lungs of C57 and S100A4 mice at 6 mo using microArrays followed by qRT-PCR. Induction of miR-466 in WT mice infected with virus (P < 0.01), was not observed in S100A4 mice. miR-466 can target the 3′ UTR of RUNX1, a transcription factor for serine elastase, and reduce its expression. The inability to reduce RUNX1 in S100A4 mice in response to viral infection may be related to elevated serine elastase activity. Our studies show that viral infection can lead to progressive neointimal formation and that the susceptibility of S100A4 mice associated with heightened elastase may be linked to differential expression of miR-466.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).