Anti-SMAD3 monoclonal antibody, clone 8G4

Rheumatic heart disease (RHD) is common in developing countries and poses a big medical challenge and burden. The pathogenesis of RHD is influenced by the triad of host, agent, and environment. Autoantigens generated from Group A Streptococcus (GAS) infection are captured by the resident dendritic cells (DCs) in the heart's valvular endothelium. DCs differentiate into antigen presenting cells (APC) in the valve interstices. APC induces activation of autoreactive T cells, which triggers inflammation and tissue fibrosis. Cardiac fibrosis is promoted through the activation of Mitogen activated protein kinases (MAPKs) and its downstream signaling, including its interaction with transforming growth factor-beta (TGF-beta) and Smad proteins. TGF-beta-induced phosphorylation of Smad2 complexes with Smad3 and Smad4, and translocates into the nucleus. Angiotensin II enhances the migration, maturation, and presentation of DC. In RHD, Angiotensin II induces fibrosis via the stimulation of TGF-beta, which further increases the binding of IL-33 to sST2 but not ST2L, resulting in the upregulation of Angiotensin II and progression of cardiac fibrosis. This cascade of inflammation and valvular fibrosis causes calcification and stiffening of the heart valves in RHD. Angiotensin converting enzyme inhibitors (ACEIs) inhibit Angiotensin II production, which in turn decreases TGF-beta expression and the onset of overt inflammatory response. This condition leads to a reduction in the sST2 as the decoy receptor to "steal" IL-33, and IL-33 binds to ST2L and results in cardioprotection against cardiac fibrosis in the pathogenesis of RHD.

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-beta signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-beta type I receptor (T beta RI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive T beta RI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC.