OxLDL increases brain and aortic VSM inflammation and contributes to vascular dysregulation and altered vasoreactivity via the LOX-1 receptor

Elevation in circulating levels of oxidized low-density lipoprotein (oxLDL) and vascular inflammation are significant risk factors for the pathogenesis of vascular diseases, such as atherosclerosis and stroke. OxLDL, via the lectin-like oxLDL receptor 1 (LOX-1), has been shown to increase inflammation and oxidative stress resulting in augmented and/or attenuated vasoreactivity responses ex vivo. However, the precise mechanistic contribution of oxLDL mediated by LOX-1 on inflammatory and oxidative stress mediators as well as vasoreactivity remains to be elucidated. We hypothesized that oxLDL via the LOX-1 receptor would increase inflammation in the vasculature which in part will contribute to altered vasoreactivity. Thoracic aortic rings (1mm) were isolated from 7-mo C57BL/6J intact male mice where endothelium intact or denuded rings were mounted in a wire myography chamber and preincubated (2h) with +/-oxLDL (50μg/dL). Cumulative force (mN) concentration-response curves to phenylephrine (PE) were generated in the continued presence of oxLDL and from these curves the EC50 was determined and used to contract rings to assess acetylcholine (ACh) dependent responses. BI-0115 (10μM; selective LOX-1 inhibitor) was used to determine LOX-1 receptor dependence. Utilizing in vitro experiments, male human aortic and brain vascular smooth cells (HAoVSMCs and HBVSMCs) were conditioned with oxLDL (12h; 50 and 25μg/dL) and then treated with BI-0115 for 6h in the continued presence of +/-oxLDL. Vascular pro-inflammatory markers, COX-2 and IL-1β, were assessed using qRT-PCR. In endothelial intact aortic rings, we observed that oxLDL increased PE-contraction and these responses were LOX-1 and endothelial dependent. Additionally, we observed that oxLDL attenuated ACh-relaxation in endothelial intact rings a LOX-1 dependent manner. Together these data suggest that oxLDL via LOX-1 elicits endothelial dysregulation which could in part contribute to augmented contractility. We next examined the role of oxLDL on VSM-derived inflammatory mediators which could be in part underlying the observed enhanced aortic ring contractile response. In HAoVSMC we observed a decrease in COX-2 mRNA following exposure to BI-0115 with low dose oxLDL. Moreover, in the HBVSMCs, we observed that oxLDL alone increased mRNA levels of COX-2 and IL-1β in a dose and LOX-1 dependent manner. Together these data suggest that oxLDL/LOX-1 increases VSM-derived inflammation and endothelial dysregulation which together contribute to increased contractility. We further conclude that LOX-1 inhibition and the resulting attenuation of VSM inflammatory mediators and altered endothelial/VSM vasoreactivity, suggests that LOX-1 may be a viable target for maintaining vessel homeostasis in cardiovascular diseases. University of Arizona Valley Research Partnership Grant VRP37 P2 (RJG), American Heart Association 19AIREA34480018 (RJG). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.