Project Details
Projekt
Characterization of Cardioprotection and Immunmodulation by FOXO3a as a Master Regulator of Adiponectin
Subject Area
Cardiology, Angiology
Immunology
Immunology
Term
from 2015 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 264558061
Adiponectin (APN) is a cytokine mainly produced by adipocytes but also expressed in the heart and abundantly present in human plasma. This project has been initiated during the 2nd funding period of the CRC Transregio 19 to study cardioprotective and immunmodulatory effects of APN in vitro, in viral and autoimmune myocarditis mouse models as well as in DCMi patients. DCMi patients showed elevated cardiac and systemic APN expression. Remarkably, DCMi patients with high APN levels exhibited significantly decreased inflammation and better outcome at follow-up. In line with these findings, APN gene transfer in mice with autoimmune myocarditis diminished the expression of chemokines and pro-inflammatory cytokines confining cardiac inflammation. In cardiac myocytes and fibroblasts APN inhibited the expression of a TLR4 dependent inflammatory phenotype. In T cells, APN was characterized as a negative regulator of antigen-specific cytokine response and proliferation. In a similar manner, inhibition of NK cell function by APN in vitro and in vivo has been determined. In conclusion our data implicate that APN functions as a negative regulator of innate and adaptive immunity and inhibits the inflammatory process in DCMi/myocarditis resulting in improved outcome. Furthermore, in vitro murine and human data provide evidence of APN being directly involved in cardiac remodeling by regulating MMP-9 expression. These data suggest that APN up-regulation is a promising therapeutic approach to ameliorate cardiovascular inflammation. Importantly, we could identify the Forkhead transcription factor FOXO3a as a master regulator of APN expression. Little is known so far about the effects of modulation of FOXO3a function in the cardiovascular system. We have previously shown that Foxo3a inhibits the hypertrophic response in cardiac myocytes and preliminary data suggest involvement of Foxo3a in cardiac remodeling and Redox-detoxification. Moreover, Foxo3a is currently studied for its regulatory role in innate and adaptive immune responses. The characterization of FOXO3a function in cardiovascular inflammatory as well as cardiac remodeling processes is the objective of this proposal (originally submitted for the 3rd funding period within the CRC/TR19). Effects of FOXO3a modulation will be analyzed in vitro and in several in vivo mouse models of cardiac inflammation and injury. In patients with cardiomyopathy, acute MI and cardiac allograft rejection FOXO3a expression/activation status as well as FOXO3a polymorphisms will be correlated with immune and outcome parameters. Finally, the impact of therapeutic modulation of FOXO3a on the immune response as well as cardiac remodeling will be studied in murine animal models. Since adiponectin targeting therapies are presently not feasible but modulators of FOXO3a function are currently being developed in oncology, this approach has a high potential for clinical translation.
DFG Programme
Research Grants
