Adam W Akerman1, Robert E Stroud1, Ryan W Barrs1, R Tyler Grespin2, Lindsay T McDonald3, R Amanda C LaRue3, Rupak Mukherjee4, John S Ikonomidis2, Jeffery A Jones5, Jean Marie Ruddy6. 1. Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC. 2. Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC. 3. Medical University of South Carolina, Division of Pathology and Laboratory Medicine, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. 4. Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. 5. Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC; Ralph H. Johnson VAMC, Charleston, SC. 6. Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC. Electronic address: ruddy@musc.edu.
Abstract
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 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. 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.
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 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. 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.
Authors: A D Protogerou; E Zampeli; K Fragiadaki; K Stamatelopoulos; C Papamichael; P P Sfikakis Journal: Atherosclerosis Date: 2011-09-16 Impact factor: 5.162
Authors: J Juvonen; H M Surcel; J Satta; A M Teppo; A Bloigu; H Syrjälä; J Airaksinen; M Leinonen; P Saikku; T Juvonen Journal: Arterioscler Thromb Vasc Biol Date: 1997-11 Impact factor: 8.311
Authors: A E Koch; S L Kunkel; W H Pearce; M R Shah; D Parikh; H L Evanoff; G K Haines; M D Burdick; R M Strieter Journal: Am J Pathol Date: 1993-05 Impact factor: 4.307
Authors: Jean Marie Ruddy; Jeffrey A Jones; Robert E Stroud; Rupak Mukherjee; Francis G Spinale; John S Ikonomidis Journal: Circulation Date: 2009-09-15 Impact factor: 29.690
Authors: Ricardo C Ferreira; Daniel F Freitag; Antony J Cutler; Joanna M M Howson; Daniel B Rainbow; Deborah J Smyth; Stephen Kaptoge; Pamela Clarke; Charlotte Boreham; Richard M Coulson; Marcin L Pekalski; Wei-Min Chen; Suna Onengut-Gumuscu; Stephen S Rich; Adam S Butterworth; Anders Malarstig; John Danesh; John A Todd Journal: PLoS Genet Date: 2013-04-04 Impact factor: 5.917
Authors: Karlijn B Rombouts; Tara A R van Merrienboer; Johannes C F Ket; Natalija Bogunovic; Jolanda van der Velden; Kak Khee Yeung Journal: Eur J Clin Invest Date: 2021-11-21 Impact factor: 5.722