PMID- 29107003 OWN - NLM STAT- MEDLINE DCOM- 20180725 LR - 20200218 IS - 1615-5947 (Electronic) IS - 0890-5096 (Print) IS - 0890-5096 (Linking) VI - 46 DP - 2018 Jan TI - Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation. PG - 193-204 LID - S0890-5096(17)31039-7 [pii] LID - 10.1016/j.avsg.2017.10.001 [doi] AB - BACKGROUND: 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). METHODS: An IL-6 infusion model (4.36 mug/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. RESULTS: 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. CONCLUSIONS: 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. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Akerman, Adam W AU - Akerman AW AD - Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC. FAU - Stroud, Robert E AU - Stroud RE AD - Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC. FAU - Barrs, Ryan W AU - Barrs RW AD - Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC. FAU - Grespin, R Tyler AU - Grespin RT AD - Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC. FAU - McDonald, Lindsay T AU - McDonald LT AD - Medical University of South Carolina, Division of Pathology and Laboratory Medicine, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. FAU - LaRue, R Amanda C AU - LaRue RAC AD - Medical University of South Carolina, Division of Pathology and Laboratory Medicine, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. FAU - Mukherjee, Rupak AU - Mukherjee R AD - Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. FAU - Ikonomidis, John S AU - Ikonomidis JS AD - Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC. FAU - Jones, Jeffery A AU - Jones JA AD - Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. FAU - Ruddy, Jean Marie AU - Ruddy JM AD - Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC. Electronic address: ruddy@musc.edu. LA - eng GR - I01 BX000904/BX/BLRD VA/United States GR - R01 HL102121/HL/NHLBI NIH HHS/United States PT - Comparative Study PT - Journal Article DEP - 20171026 PL - Netherlands TA - Ann Vasc Surg JT - Annals of vascular surgery JID - 8703941 RN - 0 (Antigens, CD) RN - 0 (Antigens, Differentiation) RN - 0 (Antigens, Differentiation, Myelomonocytic) RN - 0 (CD11b Antigen) RN - 0 (CD68 protein, mouse) RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Interleukin-6) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 0 (interleukin-6, mouse) RN - 0 (monocyte-macrophage differentiation antigen) RN - 11128-99-7 (Angiotensin II) SB - IM MH - Angiotensin II MH - Animals MH - Antigens, CD/metabolism MH - Antigens, Differentiation/metabolism MH - Antigens, Differentiation, Myelomonocytic/metabolism MH - Aorta, Abdominal/*metabolism/pathology/physiopathology MH - Aortic Aneurysm, Abdominal/chemically induced/*metabolism/pathology/physiopathology MH - *Arterial Pressure MH - CD11b Antigen/metabolism MH - Cells, Cultured MH - Chemokine CCL2/genetics/metabolism MH - Dilatation, Pathologic MH - Disease Models, Animal MH - Female MH - Interleukin-6/genetics/*metabolism MH - Macrophages/metabolism/pathology MH - Male MH - Mechanotransduction, Cellular MH - Mice MH - Monocytes/metabolism/pathology MH - Muscle, Smooth, Vascular/metabolism/pathology MH - Myocytes, Smooth Muscle/metabolism/pathology MH - Phosphorylation MH - STAT3 Transcription Factor/metabolism MH - Stress, Mechanical PMC - PMC5894101 MID - NIHMS950007 EDAT- 2017/11/07 06:00 MHDA- 2018/07/26 06:00 PMCR- 2018/04/11 CRDT- 2017/11/07 06:00 PHST- 2017/03/20 00:00 [received] PHST- 2017/09/10 00:00 [revised] PHST- 2017/10/05 00:00 [accepted] PHST- 2017/11/07 06:00 [pubmed] PHST- 2018/07/26 06:00 [medline] PHST- 2017/11/07 06:00 [entrez] PHST- 2018/04/11 00:00 [pmc-release] AID - S0890-5096(17)31039-7 [pii] AID - 10.1016/j.avsg.2017.10.001 [doi] PST - ppublish SO - Ann Vasc Surg. 2018 Jan;46:193-204. doi: 10.1016/j.avsg.2017.10.001. Epub 2017 Oct 26.