Wang Min Ph.D., University of Wales, UK
Associate Professor of Pathology
Research Interests
Inflammation; Angiogenesis; Atherosclerosis; Transplant rejection; Tumor metastasis
Research Summary
Myocardial infarction due to atherosclerosis of coronary arteries remains the leading cause of death in the United States. Excessive/chronic inflammatory responses (e.g., TNF) and increases in reactive oxygen species (ROS) represent common pathogenic mechanism for atherosclerosis. The vascular cell that primarily limits the inflammatory and atherosclerotic process is the vascular endothelial cells (EC). Inflammation/ROS induces EC dysfunction by disturbing normal homeostasis, relaxation and survival. These defects in EC function are mediated by cytokine/redox-regulated signal transduction and gene transcription. The primary goal in my laboratory is to dissect signal pathways during inflammatory responses and develop therapeutic targets for treatment of vascular diseases. We have focused on the following areas of inflammation: 1. To dissect TNF signaling pathways in EC. 2. To understand how shear stress inhibits TNF signaling to function as an atheroprotective factor. 3. To define the role of inflammation/oxidative stress in vascular diseases including atherosclerosis, graft arteriosclerosis, insulin resistance, and cardiomyopathy/heart failure. 4. To determine the mechanism of inflammation/ischemia-induced angiogenesis/arteriogenesis and vascular remodeling. In the first two areas, we have focused on apoptosis signal-regulating kinase (ASK1), a member of MAP3Ks mediating stress-activated kinase (JNK/p38) cascades. We have elucidated the mechanisms for ASK1 activation by various stresses (TNF, ROS and DNA damaging agents). Moreover, ASK1 is a target of laminar flow. While TNF/ROS activates ASK1, atheroprotective laminar flow inhibits ASK1 and ASK1-induced EC activation and apoptosis. We are now identifying signal transducers mediating the function of shear stress. We have recent identified new protein AIP1, a new member of Ras-GAP family protein, is a potential candidate. In the third area, we have shown that inflammation-induced mitochondria dysfunction (ROS generation) and intracellular kinase cascades play critical roles in causing EC dysfunction characterized by reduction of nitric oxide (NO) bioavailability, insulin sensitivity and EC survival. However, cellular anti-oxidant thioredoxin proteins (particularly the mitochondrial form) are critical regulators of inflammation/oxidative stress in EC. In the fourth area, we have demonstrated that antiangiogenic gene therapy inhibits progression of angiogenesis-dependent diseases such as cancer and rheumatoid arthritis in animal models. We have further identified TNFR2-Bmx-VEGFR2-mediated angiogenic pathway plays a critical role in inflammation/ischemic-induced angiogenesis/arteriogenesis and tumor metastases.
Extensive Research Description
The primary goal in my laboratory is to dissect signal pathways during inflammatory responses and develop therapeutic targets for treatment of vascular diseases. We have focused on the following areas of inflammation:
- To dissect TNF signaling pathways in EC
- To understand how shear stress inhibits TNF signaling to function as an atheroprotective factor
- To define the role of inflammation/oxidative stress in vascular diseases including atherosclerosis, graft arteriosclerosis, insulin resistance, and cardiomyopathy/heart failure.
- To determine the mechanism of inflammation?/ischemia-induced angiogenesis/arteriogenesis and vascular remodeling
In the first two areas, we have focused on apoptosis signal-regulating kinase (ASK1), a member of MAP3Ks mediating stress-activated kinase (JNK/p38) cascades. In the third area, we have shown that inflammation-induced mitochondria dysfunction play a critical role in causing EC dysfunction, characterized by reduction of nitric oxide (NO) bioavailability. In the fourth area, we have found that a TNFR2-Bmx-VEGFR2-mediated angiogenic pathway plays a critical role in angiogenesis?/arteriogenesis.
Selected Publications
- Yu, L., Min, W.* He, Y, Qin, L., Zhang, H., Bennett, AM, and Chen, H (2009) JAK2 and SHP2 reciprocally regulate tyrosine phosphorylation and stability of proapoptotic protein ASK1. J. Biol. Chem. 284(20):13481-8. PMCID: PMC 2679448.
- Chen, H., Ko, G., Zatti, A., di Giacomo, G., Liu, L., Raiteri, E., Perucco, E., Collesi, C., Min, W., Zeiss, C., De Camilli, P. and Cremona, O (2009). Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice. Proc. Natl. Acad. Sci. USA 106(33), 13838-43. PMCID: PMC2728981.
- Xie, D., Gore, C., Zhou, J., Pong, RC, Zhang, H., Yu, L., Vessella, RL, Min, W., and Hsieh, JT (2009). DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc. Natl. Acad. Sci. USA 106(33), 13838-43. PMCID: PMC2785260.
- Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516.
- Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516
- Xie, D., Gore, C., Liu, J., Pong, RC, Mason, R., Hao, G., Long, M., Kabbani, W., Yu, L., Zhang, H., Chen, H., Sun, X., Boothman, Min, W.*, and Hsieh, JT* (2010). DAB2IP/AIP1 modulates epithelial-to-mesenchymal transition (EMT) and metastasis in prostate cancer Proc. Natl. Acad. Sci. USA 107 (6):2485-90. (*co-corresponding authors). PMCID: PMC2823864.
- He, Y, Zhang, H., Yu, L., Gunel, M., Boggon, T., Chen, H. and Min, W.* (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Science Signaling. 3 (116):ra26. PMCID: PMC3052863.
- Kumar A, Hou X, Lee C, Li Y, Maminishkis A, Tang Z, Zhang F, Langer HF, Arjunan P, Dong L, Wu Z, Zhu LY, Wang L, Min W, Colosi P, Chavakis T, Li X. (2010) Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation. J Biol Chem. 14;285(20):15500-10. PMCID: PMC2865282.
- Luo, Y, Xu, Z., Wan, T, He, Y, Jones, D., Zhang, H, and Min, W*. (2010) Endothelial-specific transgenesis of TNFR2 promotes adaptive arteriogenesis and angiogenesis Arterioscler Thromb Vasc Biol. 30 (7): 1307-14. PMCID: PMC2889154
- Yu, L., Ji, W., Zhang, H., Renda, MJ, He, Y., Lin, S., Cheng, E., Chen, H., Krause, DS, and Min, W.* (2010). SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J. Exp Med. 207(6):1183-95. PMCID: PMC2882842.
Selected Publications
- Yu, L., Min, W.* He, Y, Qin, L., Zhang, H., Bennett, AM, and Chen, H (2009) JAK2 and SHP2 reciprocally regulate tyrosine phosphorylation and stability of proapoptotic protein ASK1. J. Biol. Chem. 284(20):13481-8. PMCID: PMC 2679448.
- Chen, H., Ko, G., Zatti, A., di Giacomo, G., Liu, L., Raiteri, E., Perucco, E., Collesi, C., Min, W., Zeiss, C., De Camilli, P. and Cremona, O (2009). Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice. Proc. Natl. Acad. Sci. USA 106(33), 13838-43. PMCID: PMC2728981.
- Xie, D., Gore, C., Zhou, J., Pong, RC, Zhang, H., Yu, L., Vessella, RL, Min, W., and Hsieh, JT (2009). DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc. Natl. Acad. Sci. USA 106(33), 13838-43. PMCID: PMC2785260.
- Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516.
- Wan, T., Liu, T., Zhang, H, Tang, S, and Min, W.* (2010). AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J. Biol. Chem. 285(6):3750-7. PMCID: PMC2823516
- Xie, D., Gore, C., Liu, J., Pong, RC, Mason, R., Hao, G., Long, M., Kabbani, W., Yu, L., Zhang, H., Chen, H., Sun, X., Boothman, Min, W.*, and Hsieh, JT* (2010). DAB2IP/AIP1 modulates epithelial-to-mesenchymal transition (EMT) and metastasis in prostate cancer Proc. Natl. Acad. Sci. USA 107 (6):2485-90. (*co-corresponding authors). PMCID: PMC2823864.
- He, Y, Zhang, H., Yu, L., Gunel, M., Boggon, T., Chen, H. and Min, W.* (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Science Signaling. 3 (116):ra26. PMCID: PMC3052863.
- Kumar A, Hou X, Lee C, Li Y, Maminishkis A, Tang Z, Zhang F, Langer HF, Arjunan P, Dong L, Wu Z, Zhu LY, Wang L, Min W, Colosi P, Chavakis T, Li X. (2010) Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation. J Biol Chem. 14;285(20):15500-10. PMCID: PMC2865282.
- Luo, Y, Xu, Z., Wan, T, He, Y, Jones, D., Zhang, H, and Min, W*. (2010) Endothelial-specific transgenesis of TNFR2 promotes adaptive arteriogenesis and angiogenesis Arterioscler Thromb Vasc Biol. 30 (7): 1307-14. PMCID: PMC2889154
- Yu, L., Ji, W., Zhang, H., Renda, MJ, He, Y., Lin, S., Cheng, E., Chen, H., Krause, DS, and Min, W.* (2010). SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J. Exp Med. 207(6):1183-95. PMCID: PMC2882842.
- Li X, Zhang R, Zhang H, He Y, Ji W, Min W*, Boggon TJ*. (2010) Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem. 285(31):24099-107 (*co-corresponding author). PMCID: PMC2911348.
- Sison, K., Eremina, V., Baelde, H., Min, W., Hirashima, M., Fantus, IG, Quaggin, SE (2010) Glomerular structure and function require paracrine, not autocrine, VEGF-VEFR2 signaling. J Am Soc Nephrol 21(10): 1691-710. PMCID: PMC3013545.
- Jones, D, Xu, Z, Zhang, H., He, Y, Kluger, M, Chen, H., and Min, W*. (2010) Functional analyses of the non-receptor kinase Bmx in VEGF-induced lymphangiogenesis. Arterioscler Thromb Vasc Biol. 30(12):2553-61. . PMCID: PMC3106279.
- Louvi, A., Chen, L., Two, A., Zhang, H., Min, W., and Gunel, M (2011). Ccm3 ablation in neurovascular unit astrocytes leads to formation of cerebral cavernous malformations. Proc. Natl. Acad. Sci. USA. 108(9):3737-42. PMCID: PMC3048113.
- Li X, Ji W, Zhang R, Folta-Stogniew E, Min W, Boggon TJ. Molecular recognition of leucine-aspartate repeat (LD) motifs by the focal adhesion targeting-homology domain of cerebral cavernous malformation 3 (CCM3). J Biol Chem. 286(29):26138-47. PMCID: PMC3138288.
- Yu, L., Qin, L., Zhang, H., He, Y., Chen, H., Pober, J.S., Tellides, G., Min, W*. (2011) AIP1 prevents arteriosclerosis by inhibiting IFN-?-dependent smooth muscle cell proliferation and intimal expansion. Cir Res. 109(4):418-27. PMCID: PMC3227522.
- Jones, D, Li, Y, He, Y, Xu, Z, Chen, H, Min W*. (2012) Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis. Arterioscler Thromb Vasc Biol. 32(3):633-42. PMCID: PMC32288963.
- Truman LA, Bentley KL, Smith EC, Massaro SA, Gonzalez DG, Haberman AM, Hill M, Jones D, Min W, Krause DS, Ruddle NH. (2012) ProxTom lymphatic vessel reporter mice reveal prox1 expression in the adrenal medullar, megakaryocytes, and platelets. Am J Pathol. 180(4):1715-25
- Liang, XL., Zhou, H., Ding, Y., Yang, C., He, Y., Xu, Z., Luo, Y., Li, S., Sun, G., Liao, X., Min, W. (2012) TMP prevents retinal neovascularization and imparts neuroprotection in an oxygen-induced retinopathy model. Invest Ophthalmol Vis Sci. 53(4):2157-69.
- Holopainen, T., Alpuche, VL., Zheng, W., Heljasvaara, R., Jones, D., He, Y., Tvorogov, D., D’Amico, G., Wiener, Z., Andersson, LC., Pihlajaniemi, T., Min, W., and Alitalo, K. (2012) Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth. Cancer Res. 2012 May 16. [Epub ahead of print].
