Jung S. Huang
Ph.D., National Taiwan University College of Medicine (Biochemistry)
Department: Biochemistry and Molecular Biology
Academic Rank: Professor
Phone: 314-977-9250 Fax: 314-977-9205
Lab Web Page Links: biochemweb.slu.edu/people/faculty/huang.shtml
Primary Area of Cardiovascular Research Interest
-Role of the Anti-inflammatory Cytokine TGF-beta in Atherosclerosis
Related Areas of Cardiovascular Research Interest
-TGF-beta enhancers are a new class of anti-inflammatory agents
-Molecular Mechanisms that underlie the transport of fluid and cells (immune cells and cancer cells) from the interstitial space into lymphatic vessel lumens (termed interstitial-lymphatic transport or lymphatic entry)
-Roles of TGF-beta in other human diseases including cancer
Summary of Cardiovascular Research Interest
Transforming growth factor-beta (TGF-beta) is a family of structurally homologous dimeric proteins (three mammalian isoforms: TGF-beta1, TGF-beta2, and TGF-beta3). TGF-beta regulates multiple biological processes, including cell proliferation, extracellular matrix (ECM) synthesis, angiogenesis, immune response, apoptosis and differentiation. It plays a crucial role in the pathogenesis of many human diseases, including cancer, cardiovascular disease, tissue fibrosis, autoimmune diseases, and other disease or disorders. TGF-beta is a tumor suppressor in early stages of tumorigenesis. Loss of the TGF-beta growth inhibitory response contributes to the malignancy of carcinoma cells. Many lines of evidence indicate that TGF-beta in the blood circulation is a protective cytokine against atherosclerosis. We hypothesize that hypercholesterolemia and high levels of dietary trans fats cause atherosclerosis, at least in part, by suppressing canonical TGF-beta signaling (Smad2-dependent) in aortic endothelium and that TGF-beta enhancers are valuable for preventing atherosclerosis, cancer and other diseases.
In our lab, we have investigated the effects of TGF-beta suppressors or antagonists and enhancers on atherosclerosis. We recently found that the cellular responses to TGF-beta stimulation are determined by TGF-beta type I/type II receptor (TbetaR-I/TbetaR-II) heterocomplex partitioning between clathrin-dependent and caveolae-dependent endocytosis pathways which are mediated at plasma-membrane non-lipid raft microdomains and lipid rafts/caveolae, respectively. The former results in promoting canonical signaling and cellular responses, whereas the latter leads to rapid degradation of TGF-beta-bound TbetaR-I/TbetaR-II heterocomplexes without generating canonical signaling and cellular responses. The two endocytosis pathways are mutually exclusive. The more TbetaR-I/TbetaR-II heterocomplexes are localized in non-lipid raft microdomains, the more canonical TGF-β signaling is induced. Cholesterol, alone or complexed in lipoproteins (LDL, VLDL), suppresses canonical signaling and cellular responses by increasing lipid raft and/or caveolae localization of TbetaR-I/TbetaR-II heterocomplexes and facilitating rapid degradation of TbetaR-I/TbetaR-II heterocomplexes following TGF-beta binding and thus suppressing TGF-beta-induced signaling. Conversely, cholesterol-lowering agents (e.g., fluvastatin and lovastatin) and high-density lipoproteins (HDL) enhance TGF-beta-induced signaling and cellular responses by increasing non-lipid raft microdomain localization of TbetaR-I/TbetaR-II heterocomplexes and promoting TGF-beta-induced signaling.
Clathrin-dependent endocytosis of TbetaR-I/TbetaR-II heterocomplexes is known to be involved in TGF-beta-induced signaling, but the subcellular locus at which TGF-beta induces signaling remains unclear. Recently, we demonstrated that inhibitors of clathrin-dependent endocytosis, which are known to arrest the progression of endocytosis at coated-pit stages, inhibit internalization of cell-surface TG F-beta-bound TbetaR-I/TbetaR-II heterocomplexes and prolong TGF-beta signaling at the plasma membrane. These inhibitors enhance TGF-beta-induced signaling and cellular responses (Smad2 phosphorylation/nuclear localization and expression of PAI-1). We also demonstrate that dynasore, which arrests clathrin-dpendent endocytosis at the coated-pit stage and is a potent enhancer of canonical TGF-beta signaling, effectively prevents atherosclerosis without altering high plasma cholesterol levels in ApoE-null mice with hypercholesterolemia. This finding supports the hypothesis that suppression of canonical TGF-beta signaling is an important step in atherogenesis caused by hypercholesterolemia. Dynasore appears to prevent atherosclerosis by prolonging and enhancing TGF-beta signaling at the plasma membrane and thereby antagonizing cholesterol suppression of TGF-beta-induced signaling and cellular responses.
We have recently identified many TGF-beta enhancers which affect cellular responses induced by TGF-beta at various levels (receptor, signaling, and transcription). These include synthetic compounds (e.g., dynasore, statins and vitamin D3) and natural products (e.g., alcohol, olive oil and plants containing triterpenoids, polyphenols and polyunsaturated fatty acids). Many of these natural products are known to protect people from cardiovascular disease and cancer. The discoveries of TGF-beta enhancers have led us to suggest that appropriate diets containing natural (or synthetic) TGF-beta enhancers, moderate drinking of red wine (a TGF-beta enhancer) plus exercise (which increases plasma levels of HDL, a TGF-beta enhancer) are likely to be valuable for the prevention and treatment of atherosclerosis and other human diseases.