Our laboratory studies the interactions between lipoprotein metabolism and blood clot lysis. Fibrinolysis, the primary mechanism that dissolves a blood clot, is initiated by a serine protease tissue-type plasminogen activator (tPA). Our previous study discussed a novel source and regulation of endogenous basal plasma tPA derived from hepatocytes, which is important for fibrinolysis when a vessel injury occurs (Blood, 2019). The tPA activity is inhibited primarily by the serpin plasminogen activator inhibitor 1 (PAI-1). A balance between tPA and PAI-1 in plasma is essential for preventing excessive clotting. Our study revealed the mechanism of how hepatocytes sense metabolic stresses and imbalance the production of tPA and PAI-1, influencing the degree of impaired fibrinolysis in obesity (JCI, 2020). 

A new study from our lab, discovered a direct interaction between tPA and apoB, the scaffold protein of LDL and VLDL particles, reducing VLDL production from hepatocytes and lowering atherogenic apoB-lipoprotein cholesterol in circulation (Science, 2023). The goal of our laboratory is to understand the role of hepatocyte-derived tPA and basal fibrinolysis in hemostasis, and to develop diagnostic/ preventive/ therapeutic strategies that can be used to combat atherosclerosis, thrombosis, and bleeding disorders. Specific areas of research interests include: 1) a new link between reduced fibrinolysis and dyslipidemia in atherothrombosis, 2) fibrinolysis and lipoproteins in hemophilia, 3) the role of lipoprotein in platelet biology, 4) the role of hepatocyte tPA and liver injuries, and 5) a timely study of dyslipidemia and thrombosis in COVID-19.

• AHA Collaborative Sciences Award 952422, American Heart Association
  07/01/22–06/30/27.
• R01HL163516-01, NIH/NHLBI 04/01/22–03/31/27
  Zheng Z. (PI)
  The role of hepatatocyte tPA in hepatic VLDL production.
• Startup Fund, Medical College of Wisconsin & Versiti Blood Center of Wisconsin
  07/01/20–06/30/24
  To establish a research laboratory as an independent investigator

Click Here for a full list of publications from Dr. Ze Zhang

Selected Publications

1. Dai W, Castleberry M, Zheng Z. Tale of two systems: the intertwining duality of fibrinolysis and lipoprotein metabolism. J Thromb Haemost. 2023 Oct;21(10):2679-2696. doi: 10.1016/j.jtha.2023.08.004. Epub 2023 Aug 12. Review. PubMed PMID: 37579878; PubMed Central PMCID: PMC10599797.
2. Dai W, Zhang H, Lund H, Zhang Z, Castleberry M, Rodriguez M, Kuriakose G, Gupta S, Lewandowska M, Powers HR, Valmiki S, Zhu J, Shapiro AD, Hussain MM, López JA, Sorci-Thomas MG, Silverstein RL, Ginsberg HN, Sahoo D, Tabas I, Zheng Z. Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes. Science. 2023 Sep;381(6661):eadh5207. doi: 10.1126/science.adh5207. Epub 2023 Sep 1. PubMed PMID: 37651538; PubMed Central PMCID: PMC10697821.
3. Zhang Z, Dai W, Zhu W, Rodriguez M, Lund H, Xia Y, Chen Y, Rau M, Schneider EA, Graham MB, Jobe S, Wang D, Cui W, Wen R, Whiteheart SW, Wood JP, Silverstein R, Berger JS, Kreuziger LB, Barrett TJ, Zheng Z. Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19. Res Pract Thromb Haemost. 2023 Aug;7(6):102164. doi: 10.1016/j.rpth.2023.102164. eCollection 2023 Aug. PubMed PMID: 37680312; PubMed Central PMCID: PMC10480648.
4. Kahn SR, Arnold DM, Casari C, Desch KC, Devreese KMJ, Favaloro EJ, Gaertner F, Gouw SC, Gresele P, Griffioen AW, Heger L, Kini RM, Kohli S, Leader A, Lisman T, Lordkipanidzé M, Mullins E, Okoye HC, Rosovsky RP, Salles-Crawley II, Selby R, Sholzberg M, Stegner D, Violi F, Weyand AC, Williams S, Zheng Z. Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress. Res Pract Thromb Haemost. 2023 May;7(4):100193. doi: 10.1016/j.rpth.2023.100193. eCollection 2023 May. PubMed PMID: 37538494; PubMed Central PMCID: PMC10394567.
5. Yin L, Zhou T, Zheng Z, Long X, Qiu H, Lu HS. Editorial: Women in cardiovascular therapeutics. Front Cardiovasc Med. 2023;10:1183427. doi: 10.3389/fcvm.2023.1183427. eCollection 2023. PubMed PMID: 37234374; PubMed Central PMCID: PMC10207329.
6. Zheng Z, Mukhametova L, Boffa MB, Moore EE, Wolberg AS, Urano T, Kim PY. Assays to quantify fibrinolysis: strengths and limitations. Communication from the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on fibrinolysis. J Thromb Haemost. 2023 Apr;21(4):1043-1054. doi: 10.1016/j.jtha.2023.01.008. Epub 2023 Jan 14. Review. PubMed PMID: 36759279; PubMed Central PMCID: PMC10109242.
7. Puzyrenko A, Jacobs ER, Padilla N, Devine A, Aljadah M, Gantner BN, Pan AY, Lai S, Dai Q, Rubenstein JC, North PE, Simpson PM, Willoughby RE, O'Meara CC, Flinn MA, Lough JW, Ibrahim EH, Zheng Z, Sun Y, Felix J, Hunt BC, Ross G, Rui H, Benjamin IJ. Collagen-Specific HSP47(+) Myofibroblasts and CD163(+) Macrophages Identify Profibrotic Phenotypes in Deceased Hearts With SARS-CoV-2 Infections. J Am Heart Assoc. 2023 Feb 21;12(4):e027990. doi: 10.1161/JAHA.122.027990. Epub 2023 Feb 15. PubMed PMID: 36789856; PubMed Central PMCID: PMC10111490.
8. Furon J, Yetim M, Pouettre E, Martinez de Lizarrondo S, Maubert E, Hommet Y, Lebouvier L, Zheng Z, Ali C, Vivien D. Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors. Fluids Barriers CNS. 2023 Feb 3;20(1):11. doi: 10.1186/s12987-023-00411-w. PubMed PMID: 36737775; PubMed Central PMCID: PMC9896721.
9. Shi H, Wang X, Li F, Gerlach BD, Yurdagul A Jr, Moore MP, Zeldin S, Zhang H, Cai B, Zheng Z, Valenti L, Tabas I. CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Sci Transl Med. 2022 Nov 23;14(672):eabp8309. doi: 10.1126/scitranslmed.abp8309. Epub 2022 Nov 23. PubMed PMID: 36417485; PubMed Central PMCID: PMC10199725.
10. Zheng Z, Riva N, Scarlatescu E, de Moerloose P, Ariëns R, Amigo MC; ISTH Ethics Committee. Developing and improving the ethical framework for the ISTH. J Thromb Haemost. 2022 Aug;20(8):1753-1754. doi: 10.1111/jth.15780. PMID: 35859283
11. Rodriguez M, Dai W, Lund H, Osinski K, Zhang Z, Silverstein R, Zheng Z. The correlations among racial/ethnic groups, hypertriglyceridemia, thrombosis, and mortality in hospitalized patients with COVID-19. Best Pract Res Clin Haematol. 2022 Sep;35(3):101386. doi: 10.1016/j.beha.2022.101386. Epub 2022 Oct 3. PMID: 36494155
12. Nayak L, Zheng Z. COVID-19: A hematological perspective. Best Pract Res Clin Haematol. 2022 Sep;35(3):101412. doi: 10.1016/j.beha.2022.101412. Epub 2022 Nov 4. PubMed PMID: 36494151; PubMed Central PMCID: PMC9633637.
13. Dai W, Lund H, Chen Y, Zhang J, Osinski K, Jones SZ, Kreuziger LB, López JA, Benjamin IJ, Silverstein RL, Zheng Z. Hypertriglyceridemia during hospitalization independently associates with mortality in patients with COVID-19. J Clin Lipidol. 2021 Sep-Oct;15(5):724-731. doi: 10.1016/j.jacl.2021.08.002. Epub 2021 Aug 10. PMID: 34470719
14. Zheng Z, Nakamura K, Gershbaum S, Wang X, Thomas S, Bessler M, Schrope B, Krikhely A, Liu RM, Ozcan L, López JA, Tabas I. Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity. J Clin Invest. 2020 Aug 3;130(8):4348-4359. doi: 10.1172/JCI135919. PMID: 32657780
15. Zheng Z, Nayak L, Wang W, Yurdagul A Jr, Wang X, Cai B, Lapping S, Ozcan L, Ramakrishnan R, Pestell RG, Jain MK, Tabas I. An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1. Blood. 2019 Feb 14;133(7):743-753. doi: 10.1182/blood-2018-07-864843. Epub 2018 Dec 1. PMID: 30504459