PAR2 deficiency reduces the synthesis of amyloidogenic proteins in the mouse model

Emily Parissa Ghanbari (Berlin)1, A. Dörner (Berlin)1, V. Nageswaran (Berlin)1, N. Kränkel (Berlin)1, J. Friebel (Berlin)1, A. Haghikia (Berlin)1, U. Landmesser (Berlin)1, U. Rauch-Kröhnert (Berlin)2

1Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland; 2Deutsches Herzzentrum der Charite (DHZC) Innere Medizin-Kardiologie Berlin, Deutschland


Background: Protease-activated receptors (PAR1-4) are activated by serine proteases such as thrombin, trypsin and activated factor Xa. Aging is associated with an increase in organelle dysfunction and protein misfolding, which drives cellular senescence. Serum amyloid P component (SAP) is the universal constituent of all systemic amyloid peptides and prevents their phagocytosis. Clusterin has been assigned a key role in amyloidotic cardiomyopathy as a chaperone protein responsible for clearing misfolded and aggregated peptides. SAP and clusterin expression are upregulated during amyloidosis.

Purpose: In this study, we investigated the impact of PAR2 on the synthesis of amyloidogenic proteins.

Methods: We used 8-week-old (young) and 1-year-old (aged) wild type (wt) and PAR2 knockout (PAR2ko) mice with a C57BL/6J background on a regular diet (n= 8/ group. Cell culture experiments were performed with human primary cardiac fibroblasts and HepG2 hepatocytes.

Results: Aged PAR2ko mice showed less gene and protein expression of amyloidogenic proteins SAP and clusterin. As a marker of systemic amyloid deposits, SAP was reduced by 51% in the plasma. Hepatic gene expression of SAP was reduced by 60% (p≤0.01) and clusterin by 72% (p≤0.002) in aged PAR2ko. The hepatic expression of TLR2 was also reduced by 71% (0.001) and TLR4 by 46% (p≤0.007) in aged PAR2ko, as were TNFa by 35% (p≤0.007), IL-6 by 67% (p≤0.01) and IL-1b by 60% (p≤0.007). PAR1 showed a strong negative correlation with clusterin in aged PAR2ko (r=-0.86; p≤0.007) and with SAP (r=-0.44; p≤0.009). PAR2 correlated with TLR4 (r=0.85; p≤0.004), TLR2 (r=0.77; p≤0.02) and SAP expression (r=0.63; p≤0.067). Stimulation with lipopolysaccharide (LPS) increased clusterin, vitronectin, PAR1 and PAR2 gene expression in primary cardiac fibroblasts and HepG2 hepatocytes.

Conclusion: Aged PAR2ko mice showed less hepatic expression of amyloidogenic proteins, as well as lower SAP plasma levels. PAR1 expression negatively and PAR2 expression positively correlated with the expression of amyloidogenic proteins. PAR2-TLR4 signalling may play a role in the synthesis of amyloid.

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