Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Dysregulation of p90 ribosomal S6 kinase isoform 1 impairs macrophage function during chronic angiotensin II exposure
L. Rathjens1, S. Schulz1, D. Niese1, K. M. Wrona1, M. N. Hirt1, T. Eschenhagen1, K. Stathopoulou1, F. Cuello1
1Universitätsklinikum Hamburg-Eppendorf, Hamburg;
The p90 ribosomal (RSK) family of protein kinases contributes to the regulation of fundamental physiological processes such as proliferation, growth, survival and differentiation. We found that RSK1, the isoform abundantly expressed in the heart, is susceptible to oxidation and consequently forms a homo-interprotein disulfide between two kinase monomers. The function of RSK1 oxidative modification was investigated in a constitutive interdisulfide-defective RSK1 knock-in mouse model.

Methods and results
Chronic angiotensin II (AngII) exposure for 14 days (1.1 mg/kg; n=15 per genotype) resulted in a significant reduction in ejection fraction in KI mice compared to WT littermates (WT saline 68.0%; WT AngII 58.4%; KI saline 71.2%; KI AngII 30.4%). Histological analysis revealed enhanced fibrosis by Picrosirius red staining and significantly increased cardiomyocyte area by dystrophin staining in KI hearts after AngII exposure compared to AngII treated WT littermates. RNAseq analysis revealed defective immuncell chemotaxis in the KI after AngII exposure as one of the most differentially represented pathways. Macrophage infiltration into the hearts of WT animals was significantly increased after 3 days of AngII exposure as reflected by significantly increased detection of CD68 by RT-qPCR, this was absent in KI hearts. Leukocyte and neutrophil numbers in peripheral blood in KI was lower after AngII exposure compared to WT animals. Migration of isolated peritoneal macrophages towards a chemotactic stimulus increased after AngII exposure in WT animals.  In order to analyze phagocytosis of peritoneal macrophages from KI and WT animals, the macrophages were incubated with pHrodo green zymosan bioparticles. The phagocytosis assay revealed increased phagocytosis in KI compared to WT cells. Taken together, the data show a link between impaired cardiac function and macrophage infiltration into the heart upon chronic AngII administration in a redox-deficient RSK1 KI mouse model.

The present data demonstrate a role for RSK1 oxidation in the adaptation of cardiac homeostasis to chronic neurohumoral stimulation by regulating macrophage function.