RESUMO
Fibroblast growth factors (Fgfs) are pleiotropic proteins involved in development, repair and metabolism. Fgf16 is predominantly expressed in the heart. However, as the heart function is essentially normal in Fgf16 knockout mice, its role has remained unclear. To elucidate the pathophysiological role of Fgf16 in the heart, we examined angiotensin II-induced cardiac hypertrophy and fibrosis in Fgf16 knockout mice. Angiotensin II-induced cardiac hypertrophy and fibrosis were significantly promoted by enhancing Tgf-ß1 expression in Fgf16 knockout mice. Unexpectedly, the response to cardiac remodeling was apparently opposite to that in Fgf2 knockout mice. These results indicate that Fgf16 probably prevents cardiac remodeling, although Fgf2 promotes it. Cardiac Fgf16 expression was induced after the induction of Fgf2 expression by angiotensin II. In cultured cardiomyocytes, Fgf16 expression was promoted by Fgf2. In addition, Fgf16 antagonized Fgf2-induced Tgf-ß1 expression in cultured cardiomyocytes and noncardiomyocytes. These results suggest a possible mechanism whereby Fgf16 prevents angiotensin II-induced cardiac hypertrophy and fibrosis by antagonizing Fgf2. The present findings should provide new insights into the roles of Fgf signaling in cardiac remodeling.
Assuntos
Angiotensina II/farmacologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Fatores de Crescimento de Fibroblastos/deficiência , Fatores de Crescimento de Fibroblastos/metabolismo , Fibrose/induzido quimicamente , Fibrose/metabolismo , Animais , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Células Cultivadas , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fibrose/patologia , Fibrose/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Toll-like receptors (TLRs) sense microbial infection through recognition of pathogen-associated molecular patterns. For example, TLR4 responds to the lipopolysaccharide of gram-negative bacteria, whereas TLR2 recognizes a broad range of microbial ligands. Both receptors are, therefore, compelling targets for treating sepsis. Here, we developed a TLR2xTLR4 tetravalent bispecific antibody designated ICU-1, which inhibits both receptors. The inhibitory activity of ICU-1 was comparable to that of the parental antibodies in neutralization assays using a human monocyte cell line. Moreover, ICU-1 completely blocked stimulation of human peripheral blood mononuclear cells by clinically relevant bacterial species. These findings provide convincing evidence that ICU-1 offers a novel approach for treating bacterial sepsis.