Substance P enhances the local activation of NK 1 R-expressing c-kit + cardiac progenitor cells in right atrium of ischemia/reperfusion-injured heart

Background Localization of neurokinin 1 receptor (NK 1 R), the endogenous receptor for neuropeptide substance P (SP), has already been described for the right atrium (RA) of the heart. However, the biological role of SP/NK 1 R signal pathways in the RA remains unclear. Sprague-Dawley rats were randomly divided into 4 groups ( n = 22 each); subjected to sham, ischemia/reperfusion-injury (I/R), I/R with 5 nmole/kg SP injection (SP + I/R), and SP + I/R with 1 mg/kg RP67580 injection (RP, a selective non-peptide tachykinin NK 1 R antagonist) (RP/SP + I/R). The left anterior descending coronary artery was occluded for 40 min followed by 1 day reperfusion with SP or SP + RP or without either. After 1 day, both atria and ventricles as well as the heart apexes were collected. Results SP promoted the expression of c-Kit, GATA4, Oct4, Nanog, and Sox2 in only the RA of the SP + I/R rats via NK 1 R activation. In agreement with these observations, NK 1 R-expressing c-Kit + Nkx2.5 + GATA4 + cardiac progenitor cells (CPCs) in the ex vivo RA explant outgrowth assay markedly migrated out from RA 1 day SP + I/R approximately 2-fold increase more than RA 1 day I/R . Treatment of SP promoted proliferation, migration, cardiosphere formation, and potential to differentiate into cardiomyocytes. Using RP inhibitor, NK 1 R antagonist not only inhibited cell proliferation and migration but also reduced the formation of cardiosphere and differentiation of c-Kit + CPCs. Conclusion SP/NK 1 R might play a role as a key mediator involved in the cellular response to c-Kit + CPC expansion in RA of the heart within 24 h after I/R.