Cardiometabolic risks and atherosclerotic disease in ApoE knockout mice: Effect of spinal cord injury and Salsalate anti-inflammatory pharmacotherapy

Abstract

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-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), 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-1β, IL-6, TNFα, MCP-1, and CCL-5 may be effective predictors of AD.

Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury

“…While recent clinical research indicates that presentation of atherosclerotic pathology in SCI persons is not solely dependent on increased inflammatory markers [ 55 , 56 ], it may be exacerbated by increased inflammation [ 56 ]. Preclinical research using a mouse model of atherosclerotic disease ( ApoE −/− ) found that atherosclerotic lesions were significantly increased in mice with a T9 contusion injury compared to uninjured controls [ 57 ]. While the development of atherosclerosis was associated with increased plasma levels of IL-1β, TNFα, IL-6, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand-5 (CCL-5), increased MCP-1 and CCL-5 were specifically observed in SCI mice versus uninjured controls.…”

“…While the development of atherosclerosis was associated with increased plasma levels of IL-1β, TNFα, IL-6, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand-5 (CCL-5), increased MCP-1 and CCL-5 were specifically observed in SCI mice versus uninjured controls. Importantly, the use of an anti-inflammatory salicylate drug was found to prevent SCI-induced exacerbation of atherosclerosis, possibly via the reduction in TNFα, MCP-1, and CCL-5 plasma levels [ 57 ].…”

Huayu Qutan Recipe promotes lipophagy and cholesterol efflux through the mTORC1/TFEB/ABCA1‐SCARB1 signal axis

“…Evaluated the plaque formation and lipid deposition of the aorta via oil red O staining. The aortas were processed according to the method of Bigford 20 …”

The Physiology of Neurogenic Obesity: Lessons from Spinal Cord Injury Research

“…A previous report examining myostatin inhibition as a countermeasure to SCI-related atrophy demonstrated several pleiotropic effects, although no sublesional muscle improvement [96]. However, in a more recent report, myostatin inhibition using a selective neutralizing antibody had broad effects on physical, metabolic, and functional outcomes [97]. Additionally, a separate report examining the natural compound ursolic acid as an anabolic stimulator of mTOR signaling demonstrated improved sublesional muscle mass with SCI [98].…”

“…However, despite evidence showing an increased prevalence of CVD risk factors [135,137] and mortality in PwSCI [136], less is known about CVD disease progression per se in SCI. To our knowledge, only one recent study has begun to address this question, reporting in a mouse model of atherosclerosis that SCI hastens the native trajectory of and establishes component risks for atherosclerotic disease [97]. Such studies are important to gain an understanding of diseasespecific changes occurring in PwSCI, which risk factors require our greatest attention, or how to address the hazards.…”