Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation

Autor: John S. Ikonomidis, Rupak Mukherjee, R. Amanda C. Larue, R. Tyler Grespin, Ryan W. Barrs, Jean Marie Ruddy, Lindsay T. McDonald, Adam W. Akerman, Jeffery A. Jones, Robert E. Stroud
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Vascular smooth muscle
030204 cardiovascular system & hematology
Mechanotransduction
Cellular
Monocytes
Muscle
Smooth
Vascular
Mice
Aortic aneurysm
0302 clinical medicine
Medicine
Aorta
Abdominal
Phosphorylation
Cells
Cultured
Chemokine CCL2
CD11b Antigen
Angiotensin II
Abdominal aorta
General Medicine
Anatomy
Abdominal aortic aneurysm
medicine.anatomical_structure
cardiovascular system
Female
Cardiology and Cardiovascular Medicine
Dilatation
Pathologic
STAT3 Transcription Factor
medicine.medical_specialty
Myocytes
Smooth Muscle
Antigens
Differentiation
Myelomonocytic
Article
03 medical and health sciences
Antigens
CD
medicine.artery
Internal medicine
Animals
Arterial Pressure
Aorta
Interleukin-6
business.industry
Macrophages
Monocyte
medicine.disease
Antigens
Differentiation
Disease Models
Animal
030104 developmental biology
Endocrinology
Surgery
Stress
Mechanical
business
Aortic Aneurysm
Abdominal
Myograph
Zdroj: Annals of Vascular Surgery. 46:193-204
ISSN: 0890-5096
Popis: Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA).An IL-6 infusion model (4.36 μg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR.Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 ± 5.6% (P 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 ± 0.3 fold) and MCP-1 (1.51 ± 0.11 fold) expression compared to static control (P 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway.An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies.
Databáze: OpenAIRE
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