Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

ADAM10 is upregulated in human heart failure and its pharmacological and genetic inhibition improves post-MI survival and cardiac function by abolishing CX3CL1-dependent leucocyte infiltration
E. Klapproth1, P. Klose1, J. Wiedemann1, A. Witt2, S. Künzel1, K. Guan1, I. Kopaliani2, K. Lorenz3, A. El-Armouche1
1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden; 2Institut für Physiologie, Medizinische Fakultät Car Gustav Carus der TU Dresden, Dresden; 3Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg;

Background and Purpose. The membrane sheddase ADAM10 has been implicated in immune regulatory processes, upregulated in response to specific heart pathologies e.g. ischemic heart failure and elevated serum levels of the ADAM10 substrates CX3CL1 and CXCL16 have been reported following MI. The causal role of ADAM10 in cardiovascular diseases, however, has is not known yet.

Methods and Results. Our study uses human tissue biopsies, a cardiomyocyte-specific ADAM10 knockout mouse model (ADAM10 KO) and pharmacological ADAM10 inhibitors. We show that ADAM10 protein levels are elevated in patients with ischemic cardiomyopathy (2-fold) and ADAM10 mRNA expression correlates with expression of atrial (ANP) and brain natriuretic peptide (BNP) mRNA. Upon MI, cardiomyocyte-specific ADAM10 KO and ADAM10 inhibited mice (GI254023X) show significantly improved overall survival and preserved cardiac function (Fig 1a-b). ADAM10 inhibition significantly reduces IL-1 beta-driven inflammation and leucocyte infiltration as evidenced by mRNA sequencing (Fig 1c-e) and FACS analysis. Upon hypoxia, cardiomyocyte CX3CL1 is upregulated (Fig 1f) and its coprecipitation with ADAM10 is enhanced, which is resolved by ADAM10 inhibition. Moreover, we identify this novel cardiomyocyte-specific ADAM10/CX3CL1 signaling axis to regulate leucocyte migration following hypoxia (Fig 1g).

Conclusion. Our data show that pharmacological and genetic targeting of ADAM10 is highly efficient for improving post-infarction cardiac function and survival. Due to its role in regulation of the post-MI immune response and leucocyte infiltration, upregulated ADAM10 could be a potential molecular target to be blocked in patients after MI.


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