Abstract
Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel ApoE-/- knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions-pravastatin and minocycline-had distinct anti-inflammatory effects at the plaque and systemic level. We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.
Highlights
Using serial in vivo molecular magnetic resonance imaging (MRI) and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery
We found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6
We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagenpoor in the absence of ischemic myocardial injury
Summary
Data will be available on request from the authors. This study was performed only with males, as it is well known that plaques develop more reproducibly and with less biological variability.[24,25] Male apolipoprotein knockout mice (ApoE−/−) at 8 to 10 weeks (n=78) of age were divided into 5 groups: (1) baseline/control group: ApoE−/− mice (n=10) were fed a normal laboratory diet for 12 weeks; (2) high-fat diet (HFD) group: ApoE−/− mice (n=24) were fed a HFD for 12 weeks containing 21% fat from lard and 0.15% (wt/wt) cholesterol (Special Diet Services, United Kingdom); (3) HFD+injury group: ApoE−/− mice (n=24) underwent aortic injury of the abdominal aorta as previously Highlights Sustained aortic inflammation, triggered by focal aortic injury, resulted in the formation of larger and more permeable remote atheroma with higher inflammatory cell count, larger necrotic core, and reduced collagen content. Sustained aortic inflammation, triggered by focal aortic injury, has systemic ripple effects that promote more advanced remote atheroma via an acute increase of blood inflammatory monocytes, 24 hours following injury, and persistent elevation of serum interleukin IL (interleukin)-6 for up to 3 months following injury. Pravastatin and minocycline treatments decrease plaque burden, endothelial permeability, and monocyte count and increase collagen in the remote atheroma. The abdominal aorta and the brachiocephalic artery (BCA) were imaged 30 minutes after intravenous administration of gadolinium (Gd)-albumin (Ablavar, Lantheus Medical Imaging, North Billerica). During the second imaging session, the same vascular segments were imaged, 2 hours after intravenous administration of Gd-elastin (ESMA, Lantheus Medical Imaging, North Billerica). Following the last imaging session at 12 weeks, tissue, blood, and serum were collected from the animals that underwent MRI plus additional mice per group for ex vivo analysis using histology, flow cytometry, and Luminex assay. Blood was collected from animals at the acute phase following vascular injury (1, 2, and 7 days) to assess the systemic inflammatory response by measuring different cytokines and monocytes.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call