Short‐term LPS induces aortic valve thickening in ApoE*3Leiden mice

Abstract

Background Recently, it was shown that 12 weeks of lipopolysaccharide (LPS) administration to nonatherosclerotic mice induced thickening of the aortic heart valve (AV). Whether such effects may also occur even earlier is unknown. As most patients with AV stenosis also have atherosclerosis, we studied the short‐term effect of LPS on the AVs in an atherosclerotic mouse model. Methods ApoE*3Leiden mice, on an atherogenic diet, were injected intraperitoneally with either LPS or phosphate buffered saline (PBS), and sacrificed 2 or 15 days later. AVs were assessed for size, fibrosis, glycosaminoglycans (GAGs), lipids, calcium deposits, iron deposits and inflammatory cells. Results LPS injection caused an increase in maximal leaflet thickness at 2 days (128.4 µm) compared to PBS‐injected mice (67.8 µm; P = 0.007), whereas at 15 days this was not significantly different. LPS injection did not significantly affect average AV thickness on day 2 (37.8 µm), but did significantly increase average AV thickness at day 15 (41.6 µm; P = 0.038) compared to PBS‐injected mice (31.7 and 32.3 µm respectively). LPS injection did not affect AV fibrosis, GAGs and lipid content. Furthermore, no calcium deposits were found. Iron deposits, indicative for valve haemorrhage, were observed in one AV of the PBS‐injected group (a day 2 mouse; 9.1%) and in five AVs of the LPS‐injected group (both day 2‐ and 15 mice; 29.4%). No significant differences in inflammatory cell infiltration were observed upon LPS injection. Conclusion Short‐term LPS apparently has the potential to increase AV thickening and haemorrhage. These results suggest that systemic inflammation can acutely compromise AV structure.

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

“…In both wild-type mice and in the atherosclerotic ApoE*3Leiden mouse model, intraperitoneal LPS induces AV thickening, but not calcification, suggesting a role for systemic inflammation in the early stages of CAVD. 193–195 …”

Resveratrol Ameliorates Atherosclerosis Induced by High-fat Diet and LPS in ApoE-/- Mice and Inhibits the Activation of CD4+ T Cells

“…High level of serum lipids and the inflammatory status are risk factors of AS [2,28]. Feeding ApoE -/mice with HFD can induce AS and LPS injection can accelerate the progression of disease [29]. In our study, HFD companied with LPS induced dysfunction of serum lipids and formation of atherosclerotic plaque.…”

The tyrosine kinase inhibitor nilotinib targets the discoidin domain receptor DDR2 in calcific aortic valve stenosis

“…Hyperlipidaemic APOE*3Leiden.CETP transgenic mice not only develop spontaneous atherosclerosis but can also be used for induction of lesions in the aortic valve with similarities to changes observed in human CAVS (van Broekhoven et al, 2019). After 16 weeks of treatment with nilotinib (30 mg·kg −1 ), APOE*3Leiden.CETP transgenic mice developed a significant 1.2‐fold (95% CI 1.059–1.355) increase in valve thickness compared with control mice, and a similar significant increase compared with the imatinib group (Figure 1a).…”

“…Aortic valve thickening in hyperlipidaemic mice represents a model of early valvular changes with similar characteristics to human disease in terms of osteogenic activation (Aikawa et al, 2007) and valvular iron (Laguna‐Fernandez et al, 2016; van Broekhoven et al, 2019). The present study revealed that nilotinib, but not imatinib, significantly increased murine valve thickness in hyperlipidaemic APOE*3Leiden.CETP transgenic mice that have a humanized lipoprotein metabolism and exhibit aortic valve thickening at a young age (van Broekhoven et al, 2019), which represents a model of early valvular changes with similar characteristics to human CAVS disease in terms of osteogenic activation (Aikawa et al, 2007), detected through BMP2 stainings in the present study, and valvular iron (Laguna‐Fernandez et al, 2016; van Broekhoven et al, 2019). Interestingly, nilotinib‐treated mice also exhibited a higher proportion of valvular iron positivity, which has been shown to precede calcification in human stenotic aortic valves (Morvan et al, 2019).…”