Office: 843-792-9927
Lab: 843-792-6748
Fax: 843-792-4850
Email: chaoj@musc.edu
BSB-737

Research Interests

Research in this laboratory focuses on the role of the tissue kallikrein-kinin system in hypertension, cardiovascular and renal function. Tissue kallikrein is a serine proteinase that cleaves kininogen substrate to release the potent vasoactive kinin peptide. Kinin or its metabolite binds to kinin B₁ or B₂ receptors and exerts a wide spectrum of biological effects including blood pressure reduction, vasodilation and stimulation or inhibition of cell growth. Kallikrein is regulated by endogenous kallikrein-binding protein (KBP). We have discovered, purified and cloned a novel KBP, designated as "kallistatin". Kallistatin is a new member of the serine proteinase inhibitor (serpin) family and is a multi-functional protein that has a direct action on the vasculature, in addition to its interaction with tissue kallikrein. We have developed biochemical, immunological and molecular probes, and established technologies necessary for studying the role of tissue kallikrein-kinin components in cardiovascular function.  Using gene delivery approaches, we showed that local and systemic delivery of the human tissue kallikrein gene protects against cardiovascular and renal dysfunction in several genetically and experimentally-induced hypertensive animal models. The beneficial effects include prolonged reduction of blood pressure; attenuation of cardiac hypertrophy, fibrosis, infarct size, apoptosis; reduction of renal tubule disruption, glomular sclerosis, protein cast accumulation and inflammation; reduction of neointima lesions in the blood vessel after balloon angioplasy; attenuation of stroke-induced mortality after salt loading, and induction of angiogenesis in ischemic hindlimb. These effects are mediated by activation of kinin B₁ or B₂ receptors through the NO-cGMP and prostacyclin-cAMP signal pathways. We will continue to develop improved adenoviral vectors to study the role of kallikrein, kallistatin and kinin receptors by somatic gene delivery in animal models and explore the potential of gene therapy in treating human hypertensive, cardiovascular and renal diseases.

Selected Publications

• Ni, A., Yin, H., Agata, J., Yang, Z., Chao, L. and Chao, J. (2003) Overexpression of kinin B₁ receptors induces hypertensive response to Des-Arg⁹-bradykinin and susceptibility to inflammation. J. Biol. Chem., 278(2): 219-225.
• Chao, J. and Chao, L. (2002) The role of adrenomedullin in cardiovascular and renal function. Drug News Perspect., 15(8): 511-518.
• Agata, J., Chao, L., and Chao, J. (2002) Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction. Hypertension, 40(5): 653-659.
• Miao, R.Q., Agata, J., Chao, L. and Chao, J. (2002) Kallistatin is a new endogenous inhibitor of angiogenesis and tumor growth.Blood, 100(9): 3245-3252.
• Dobrzynski, E., Montanari, D., Agata, J., Zu, J., Chao, J., and Chao, L. (2002) Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats. Am. J. Physiol., 208:E1291-E1298.
• Thongboonkerd, V., Gozal, E., Sachleben Jr., L.R., Arthur, J.M., Pierce, W.M. Cai, J., Chao, J., Bader, M., Pesquero, J.B., Gozal, D., and Klein, J.B. (2002) Proteomic analysis reveals alterations in the renal kallikrein pathway during hypoxia-induced diabetic rats. J. Biol. Chem., 277: 34708-34716.
• Smith Jr., R.S., Lin, K-F, Agata, J., Chao, L. and Chao, J. (2002) Human nitric oxide synthase gene delivery promotes angiogenesis in a rat model of hindlimb ischemia. Artheriosclerosis, Thrombosis, and Vascular Biology, 22: 1279-1285.
• Emanueli, C., Bonaria Salis, M., Pinna, A., Stacca, T., Milia, A.F., Spano, A., Chao, J., Chao, L. Sciola, L., and Madeddu, P. (2002) Prevention of diabetes-induced microangiopathy by human tissue kallikrein gene transfer. Circulation, 106: 993-999.
• Yu, H., Song, Q., Freedman, B.I., Chao, J., Chao, L., Rich, S.S., and Bowden, D.W. (2002) Association of the tissue kallikrein gene promoter with ESRD and hypertension. Kidney Int., 61: 1030-1039.
• Donaldson, S.H., Hirsh, A., Li, D.C., Holloway, G., Chao, J., Boucher, R.C. and Gabriel, S.E. (2002) Regulation of the epithelial sodium channel by serine proteases in human airways. J. Biol. Chem., 277: 8338-8345.
• Narikiyo, T., Kitamura, K., Adachi, M., Miyoshi, T., Iwashita, K., Shiraishi, N., Nonoguchi, H., Chen, L-M, Chai, K.X., Chao, J., and Tomita, K. (2002) Regulation of prostasin by adlosterone in the kidney. J. Clin. Invest., 109: 401-408.
• Porcu, P., Emanueli, C., Kapatsoris, M., Chao, J., Chao, L., and Madeddu, P. (2002) Reversal of angiogenic growth factor upregulation by revascularization of lower limb ischemia. Circulation, 105: 67-72.
• Wang, C., Dobrzynski, E., Chao, J. and Chao, L. (2001) Adrenomedullin gene delivery attenuates renal damage and cardiac hypertrophy in Goldblatt hypertensive rats. Am. J. Physiol. Renal Physiol., 280(6): F964-F971.
• Chen, L.M., Skinner, M.L., Kauffman, S.W., Chao, J., Chao, L., Thaler, C.D., and Chai, K.X. (2001) Prostasin is a glycosylphosphatidylinositol-anchored active serine protease. J. Biol. Chem., 276(24): 21434-21442.
• Chao, J., Miao, R.Q., Chen, V., Chen, L.M. and Chao, L. (2001) Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling. Biol. Chem., 382(1): 15-21.
• Emmanueli, C., minasi, A., Zacheo, A., Chao, J., Chao, L., Salis, M.B., Straino, S., Tozzi, M.G., Smith, R., Gaspa, L., Bianchini, G., Stillo, F., Capogrossi, M.C., Madeddu, P. (2001) Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation, 103(1): 125-132.
• Chen, V.C., Chao, L., Pimenta, D.C., Bledsoe, G., Juliano, L. and Chao, J. (2001) Identification of a major heparin-binding site in kallistatin. J. Biol. Chem., 276(2): 1276-1284.
• Pimenta, D.C., Chen, V.C., Chao, J., Juliano, M.A., Juliano, L. (2000) Alpha 1-antichymotrypsin and kallisatin hydrolysis by human cathespin D. J. Protein Chem. 19(5): 411-418.
• Emanueli, C., Zacheo, A., Minasi, A., Chao, J., Chao, L., Salis, M.B., Stacca, T., Straino, S., Capogrossi, M.C., Mededdu, P. (2000) Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler. Thrmob. Vasc. Biol., 20(11): 2379-2385.
• Silva, J.A., Jr., Araujo, R.C., Baltatu, O., Oliveira, S.M., Tschope, C., Fink, E., Hoffman, S., Plehm, R., Chai, K.X., Chao, L., Chao, J., Ganten, D., Pesquero, J.B., and Bader, M. (2000) Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J., 14(13): 1858-1860.
• Chen, V.C., Chao, L. and Chao, J. (2000) Roles of the P1, P2, and P3 residues in determining inhibitory specificity of kallistatin toward human tissue kallikrein. J. Biol. Chem., 275(49): 38457-38466.
• Chen, V.C., Chao, L., and Chao, J. (2000) A positively charged loop on the surface of kallistatin functions to enhance tissue kallikrein inhibition by acting as a secondary binding site for kallikrein. J. Biol. Chem., 275(51): 40371-40377.
• Agata, J., Miao, R.Q., Yayama, K., Chao, L., and Chao, J. (2000) Bradykinin B(1) receptor mediates inhibition of neointima formation in rat artery after balloon angioplasty. Hypertension, 36(3): 364-370.
• Zhang, J.J., Yoshida, H., Chao, L. and Chao, J. (2000) Human adrenomedullin gene delivery protects against cardiac hypertrophy, fibrosis, and renal damage in hypertensive dahl salt-sensitive rats. Human Gene Therapy, 11(13): 1817-1827.
• Wolf, W.C., Yoshida, H., Agata, J., Chao, L. and Chao, J. (2000) Human tissue kallikrein gene delivery attenuates hypertension, renal injury, and cardiac remodeling in chronic renal failure. Kidney Int., 58(2): 730-739.
• Emanueli, C., Bonaria Salis, M., Figueroa, C., Chao, J., Chao, L., Gaspa, L., Capogrossi, M.C., Madeddu, P. (2000) Participation of kinins in the captopril-induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse. Br. J. Pharmacol., 130(5): 1076-1082.
• Chen, V.C., Chao, L. and Chao, J. (2000) Reactive-site specificity of human kallistatin toward tissue kallikrein probed by site-directed mutagenesis. Biochim. Biophys. Acta., 1479(1-2): 237-246.
• Emanueli, C., Salis, M.B., Chao, J., Chao, L., Agata, J., Lin, K-F., Munao, A., Straino, S., Minasi, A., Capogrossi, M.C., Madeddu, P. (2000) Adenovirus-mediated human tissue kallikrein gene delivery inhibits neointima formation induced by interruption of blood flow in mice. Arterioscler. Thromb. Vasc. Biol., 20(6): 1459-1466.
• Wang, D., Yoshida, H., Song, Q., Chao, L., and Chao, J. (2000) Enhanced renal function in bradykinin B(2) receptor transgenic mice. Am. J. Physiol. Renal Physiol., 278(3): F484-F491.
• Miao, R.Q., Murakami, H., Song, Q., Chao, L. and Chao, J. (2000) Kallistatin stimulates vascular smooth muscle cell proliferation and migration in vitro andneointima formation in balloon-injured rat artery. Circ. Res., 86(4): 418-424.
• Yoshida, H., Zhang, J.J., Chao, L. and Chao, J. (2000) Kallikrein gene delivery attenuates myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Hypertension, 35(Pt. 1): 25-31.
• Dobrzynski, E., Wang, C., Chao, J., and Chao, L. (2000) Adrenomedullin gene delivery attenuates hypertension, cardiac remodeling, and renal injury in deoxycorticosterone acetate-salt hypertensive rats. Hypertension, 36(6): 995-1001.