M1/M2 macrophages and associated mechanisms in congenital bicuspid aortic valve stenosis

Wang,Rui; Chen,Wen; Ma,Zhifei; Li,Liangpeng; Chen,Xin

doi:10.3892/etm.2014.1529

M1/M2 macrophages and associated mechanisms in congenital bicuspid aortic valve stenosis

Authors:
- Rui Wang
- Wen Chen
- Zhifei Ma
- Liangpeng Li
- Xin Chen
View Affiliations

Affiliations: Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
Published online on: February 10, 2014 https://doi.org/10.3892/etm.2014.1529
Pages: 935-940

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of this study was to observe macrophage infiltration in congenital bicuspid aortic valve (CBAV) stenosis. M1/M2 macrophage distribution, inflammatory cytokine expression and the role of M1 macrophages during CBAV stenosis were also explored. The experimental and control groups comprised 30 severely stenotic CBAVs and 30 severely stenotic tricuspid aortic valves (TAVs), respectively. Histological and morphological changes were assessed using hematoxylin‑eosin (HE) staining and mRNA levels of vascular endothelial growth factor (VEGF) were examined using the quantitative polymerase chain reaction. Nonspecific, M1 and M2 macrophages were monitored using cluster of differentiation (CD)68, inducible nitric oxide synthase (iNOS) and CD163 staining, respectively. Endothelial nitric oxide synthase (eNOS), interleukin (IL)‑10, arginase (Arg)‑1 and macrophage colony‑stimulating factor (M‑CSF) were also examined using immunohistochemical staining. Of note, HE staining revealed a higher cell density and neovascularization was more common in CBAVs than TAVs. At the mRNA level, VEGF expression was two‑fold higher in CBAVs relative to that in TAVs (P=0.02). Furthermore, CD68 and iNOS were significantly higher in CBAVs compared with TAVs (P=0.029 and 0.021, respectively), while CD163 expression was lower in CBAVs (P=0.033). In addition, eNOS expression was higher and Arg‑1, IL‑10 and M‑CSF expression were lower in CBAVs compared with TAVs (all P<0.0001). The present study suggested that CBAVs are associated with a higher total and M1 macrophage density and a lower M2 macrophage density than TAVs, and that M1 macrophage infiltration may contribute to calcification of CBAVs.

View Figures

View References

1	Ward C: Clinical significance of the bicuspid aortic valve. Heart. 83:81–85. 2000. View Article : Google Scholar : PubMed/NCBI
2	Michelena HI, Desjardins VA, Avierinos JF, Russo A, Nkomo VT, Sundt TM, Pellikka PA, Tajik AJ and Enriquez-Sarano M: Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation. 117:2776–2784. 2008. View Article : Google Scholar : PubMed/NCBI
3	Otto CM: Calcification of bicuspid aortic valves. Heart. 88:321–322. 2002. View Article : Google Scholar : PubMed/NCBI
4	Nigam V and Srivastava D: Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol. 47:828–834. 2009. View Article : Google Scholar : PubMed/NCBI
5	Weinberg EJ, Kaazempur and Mofrad MR: A multiscale computational comparison of the bicuspid and tricuspid aortic valves in relation to calcific aortic stenosis. J Biomech. 41:3482–3487. 2008. View Article : Google Scholar : PubMed/NCBI
6	McKellar SH, Tester DJ, Yagubyan M, Majumdar R, Ackerman MJ and Sundt TM III: Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 134:290–296. 2007. View Article : Google Scholar : PubMed/NCBI
7	Jaguin M, Houlbert N, Fardel O and Lecureur V: Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol. 281:51–61. 2013. View Article : Google Scholar : PubMed/NCBI
8	Chu EM, Tai DC, Beer JL and Hill JS: Macrophage heterogeneity and cholesterol homeostasis: classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL. Biochim Biophys Acta. 1831:378–386. 2013. View Article : Google Scholar
9	Gordon S and Taylor PR: Monocyte and macrophage heterogeneity. Nat Rev Immunol. 5:953–964. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ma J, Liu L, Che G, Yu N, Dai F and You Z: The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer. 10:1122010. View Article : Google Scholar : PubMed/NCBI
11	Johnson JL and Newby AC: Macrophage heterogeneity in atherosclerotic plaques. Curr Opin Lipidol. 20:370–378. 2009. View Article : Google Scholar : PubMed/NCBI
12	Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 8:958–969. 2008. View Article : Google Scholar : PubMed/NCBI
13	Edin S, Wikberg ML, Dahlin AM, Rutegård J, Öberg Å, Oldenborg PA and Palmqvist R: The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One. 7:e470452012. View Article : Google Scholar : PubMed/NCBI
14	Zhao M, Fu XL and Lv H: The expression of EGFR in oral lichen planus, squamous cell papilloma and squamous cell carcinoma. Shanghai Kou Qiang Yi Xue. 21:673–676. 2012.(In Chinese).
15	Goldbarg SH, Elmariah S, Miller MA and Fuster V: Insights into degenerative aortic valve disease. J Am Coll Cardiol. 50:1205–1213. 2007. View Article : Google Scholar : PubMed/NCBI
16	Yu PJ, Skolnick A, Ferrari G, et al: Correlation between plasma osteopontin levels and aortic valve calcification: potential insights into the pathogenesis of aortic valve calcification and stenosis. J Thorac Cardiovasc Surg. 138:196–199. 2009. View Article : Google Scholar
17	Soini Y, Salo T and Satta J: Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. Hum Pathol. 34:756–763. 2003. View Article : Google Scholar : PubMed/NCBI
18	Roberts WC: The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol. 26:72–83. 1970. View Article : Google Scholar : PubMed/NCBI
19	Falcone MW, Roberts WC, Morrow AG and Perloff JK: Congenital aortic stenosis resulting from a unicommisssural valve. Clinical and anatomic features in twenty-one adult patients. Circulation. 44:272–280. 1971. View Article : Google Scholar : PubMed/NCBI
20	Moreno PR, Astudillo L, Elmariah S, Purushothaman KR, Purushothaman M, Lento PA, Sharma SK, Fuster V and Adams DH: Increased macrophage infiltration and neovascularization in congenital bicuspid aortic valve stenosis. J Thorac Cardiovasc Surg. 142:895–901. 2011. View Article : Google Scholar : PubMed/NCBI
21	Winchester R, Wiesendanger M, O’Brien W, Zhang HZ, Maurer MS, Gillam LD, Schwartz A, Marboe C and Stewart AS: Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. J Immunol. 187:1006–1014. 2011. View Article : Google Scholar : PubMed/NCBI
22	Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A and Locati M: The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25:677–686. 2004. View Article : Google Scholar : PubMed/NCBI
23	Tugal D, Liao X and Jain MK: Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol. 33:1135–1144. 2013. View Article : Google Scholar : PubMed/NCBI
24	Bronte V and Zanovello P: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 5:641–654. 2005. View Article : Google Scholar : PubMed/NCBI
25	Martinez FO, Gordon S, Locati M and Mantovani A: Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 177:7303–7311. 2006. View Article : Google Scholar : PubMed/NCBI
26	Bouhlel MA, Derudas B, Rigamonti E, et al: PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6:137–143. 2007. View Article : Google Scholar : PubMed/NCBI
27	Randolph GJ, Jakubzick C and Qu C: Antigen presentation by monocytes and monocyte-derived cells. Curr Opin Immunol. 20:52–60. 2008. View Article : Google Scholar : PubMed/NCBI
28	Dorfmüller P, Bazin D, Aubert S, Weil R, Brisset F, Daudon M, Capron F and Brochériou I: Crystalline ultrastructures, inflammatory elements, and neoangiogenesis are present in inconspicuous aortic valve tissue. Cardiol Res Pract. 2010:6859262010.PubMed/NCBI