Characterization of LCN2 in Ischemic stroke by Distal and Proximal Intraluminal Sampling

Abstract

IntroductionLipocalin‐2(LCN2) is a protein shown to be involved in many cellular processes, including the regulation of iron homeostasis, promotion of protective mechanisms in renal ischemia, and astrocyte activation in ischemic stroke. In some ischemic stroke models, LCN2 has been described as a “help me” signal, leading to the activation of microglia, astrocytes, and drive towards cellular phenotypes favorable of recovery. While some models suggest pro‐recovery effects of LCN2, other models illustrate LCN2 as having a critical role in neuroinflammation and reperfusion injury. The possibility of disease state‐dependent influence of LCN2 activity in ischemic stroke has been recognized, but has yet to be further characterizedMethodsPlasma samples were processed in accordance with the Blood and Clot Thrombectomy Registry and Collaboration BACTRAC protocol (clinicaltrials.gov NCT03153683), and underwent Proximity Extension Assay (PEA) via Olink (Olink Proteomics, Boston, MA). For each protein intracranial expression distal to the stroke thrombus was compared to the same subject’s systemic arterial blood as an internal control. Comorbidities and sex difference were analyzed using appropriate two‐way comparisons and regression.Results25 adult patients (>18yrs) were included in the study, of which 15 (60%) were female. Median age was 64 (24–91). 16 patients (64%) had hypertension, 15 patients (60%) had BMI > 25, 10 patients (40%) had a history of smoking, 6 patients (24%) had previous stroke, 4 patients (16%) had hyperlipidemia, and 1 patient (4%) had previous MI. Mean infarct time was 513 ± 246 minutes and mean infarct volume was 58,172 ± 82,284 mm3. Mean volume of edema was 62178± 87824 Of the 184 proteins tested by Olink the expression of LCN2 exhibited the greatest increase in intracranial blood distal to the thrombus when adjusted to the systemic arterial blood. LCN2 was significant for those reported having hypertension (two‐tailed, P =.024), particularly women with hypertension (two‐tailed, P =.037), males who smoked (two‐tailed, P = .078), and females who had a BMI >25 (two‐tailed, P = .078). Infarcts that measure greater than 133cm3 are associated with unfavorable functional outcomes (Boers et al., Ischemic Stroke, 2018). Using this cutoff for large infarct, LCN2 was found to be significantly increased in the intracranial ischemic blood adjusted to the systemic control (p=0.45).ConclusionsChanges of LCN2 in correspondence to women with hypertension, males who smoked, females with a BMI >25, and infarct size demonstrate gender differences and influences of certain health‐risks. For the first time, these data will provide individual insight on the molecular response to stroke in the human patient based on sex and comorbidities. Future studies will focus on the role of proteins as they relate to radiographic, functional and other clinical outcomes. Proteomic findings coupled with advanced database analysis will elucidate complex cell signaling and biomolecular interactions that occur in the blood at the site of infarct.Support or Funding Information University of Kentucky Center for Clinical and Translational Science