PMID- 33626069 OWN - NLM STAT- MEDLINE DCOM- 20210907 LR - 20240226 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 16 IP - 2 DP - 2021 TI - Cardiometabolic risks and atherosclerotic disease in ApoE knockout mice: Effect of spinal cord injury and Salsalate anti-inflammatory pharmacotherapy. PG - e0246601 LID - 10.1371/journal.pone.0246601 [doi] LID - e0246601 AB - OBJECTIVE: To test in mice with a double mutation of the ApoE gene (ApoE-/-) whether spinal cord injury (SCI) hastens the native trajectory of, and established component risks for, atherosclerotic disease (AD), and whether Salsalate anti-inflammatory pharmacotherapy attenuates the impact of SCI. METHODS: ApoE-/- mice were anesthetized and underwent a T9 laminectomy. Exposed spinal cords were given a contusion injury (70 k-dynes). Sham animals underwent all surgical procedures, excluding injury. Injured animals were randomized to 2 groups: SCI or SCI+Salsalate [120 mg/Kg/day i.p.]. Mice were serially sacrificed at 20-, 24-, and 28-weeks post-SCI, and body mass was recorded. At sacrifice, heart and aorta were harvested intact, fixed in 10% buffered formalin, cleaned and cut longitudinally for en face preparation. The aortic tree was stained with oil-red-O (ORO). AD lesion histomorphometry was calculated from the proportional area of ORO. Plasma total cholesterol, triglycerides and proatherogenic inflammatory cytokines (PAIC's) were analyzed. RESULTS: AD lesion in the aortic arch progressively increased in ApoE-/-, significant at 24- and 28-weeks. AD in SCI is significantly greater at 24- and 28-weeks compared to time-controlled ApoE-/-. Salsalate treatment attenuates the SCI-induced increase at these time points. Body mass in all SCI groups are significantly reduced compared to time-controlled ApoE-/-. Cholesterol and triglycerides are significantly higher with SCI by 24- and 28-weeks, compared to ApoE-/-, and Salsalate reduces the SCI-induced effect on cholesterol. PAIC's interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (CCL-5) are significantly greater with SCI compared to ApoE-/- at varying timepoints. Salsalate confers a marginal reducing effect on PAIC's by 28-weeks compared to SCI. Regression models determine that each PAIC is a significant and positive predictor of lesion. (p's <0.05). CONCLUSIONS: SCI accelerates aortic AD and associated risk factors, and anti-inflammatory treatment may attenuate the impact of SCI on AD outcomes. PAIC's IL-1beta, IL-6, TNFalpha, MCP-1, and CCL-5 may be effective predictors of AD. FAU - Bigford, Gregory E AU - Bigford GE AUID- ORCID: 0000-0001-8990-3465 AD - Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America. FAU - Szeto, Angela AU - Szeto A AD - Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America. FAU - Kimball, John AU - Kimball J AD - Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America. FAU - Herderick, Edward E AU - Herderick EE AD - EEH, LLC, Pickerington, Ohio, United States of America. FAU - Mendez, Armando J AU - Mendez AJ AD - Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America. FAU - Nash, Mark S AU - Nash MS AD - Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America. AD - Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida, United States of America. AD - Department of Physical Therapy, University of Miami, Coral Gables, Florida, United States of America. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210224 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Cytokines) RN - 0 (Lipids) RN - 0 (Salicylates) RN - V9MO595C9I (salicylsalicylic acid) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology/*therapeutic use MH - Aorta, Thoracic/pathology MH - Atherosclerosis/*drug therapy/*metabolism/pathology MH - Body Weight/drug effects MH - *Cardiometabolic Risk Factors MH - Cytokines/metabolism MH - Inflammation/pathology MH - Lipids/blood MH - Mice, Knockout, ApoE MH - Regression Analysis MH - Risk Factors MH - Salicylates/pharmacology/*therapeutic use MH - Spinal Cord Injuries/*drug therapy/pathology MH - Mice PMC - PMC7904230 COIS- The authors have read the journal's policy and have the following competing interests: EEH is the owner of EEH, LLC. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare. EDAT- 2021/02/25 06:00 MHDA- 2021/09/08 06:00 PMCR- 2021/02/24 CRDT- 2021/02/24 17:09 PHST- 2020/10/01 00:00 [received] PHST- 2021/01/21 00:00 [accepted] PHST- 2021/02/24 17:09 [entrez] PHST- 2021/02/25 06:00 [pubmed] PHST- 2021/09/08 06:00 [medline] PHST- 2021/02/24 00:00 [pmc-release] AID - PONE-D-20-30618 [pii] AID - 10.1371/journal.pone.0246601 [doi] PST - epublish SO - PLoS One. 2021 Feb 24;16(2):e0246601. doi: 10.1371/journal.pone.0246601. eCollection 2021.