Abstract
BackgroundLocalization of neurokinin 1 receptor (NK1R), 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/NK1R 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 NK1R 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.ResultsSP promoted the expression of c-Kit, GATA4, Oct4, Nanog, and Sox2 in only the RA of the SP + I/R rats via NK1R activation. In agreement with these observations, NK1R-expressing c-Kit+ Nkx2.5+GATA4+ cardiac progenitor cells (CPCs) in the ex vivo RA explant outgrowth assay markedly migrated out from RA1 day SP + I/R approximately 2-fold increase more than RA1 day I/R. Treatment of SP promoted proliferation, migration, cardiosphere formation, and potential to differentiate into cardiomyocytes. Using RP inhibitor, NK1R antagonist not only inhibited cell proliferation and migration but also reduced the formation of cardiosphere and differentiation of c-Kit+ CPCs.ConclusionSP/NK1R 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.
Highlights
Localization of neurokinin 1 receptor (NK1R), the endogenous receptor for neuropeptide substance P (SP), has already been described for the right atrium (RA) of the heart
Injured heart through NK1R and pluripotency gene expression Echo showed that exogenous SP significantly reduced infarct size and improved left ventricle (LV) functional recovery in an I/ R-injured heart (Fig. S1A), which is consistent with previous studies [9, 10]
TTC staining demonstrated that the infarct size of SP + I/R hearts at 7 days significantly decreased by 20% (Fig. S1B)
Summary
Localization of neurokinin 1 receptor (NK1R), the endogenous receptor for neuropeptide substance P (SP), has already been described for the right atrium (RA) of the heart. Echocardiography, computed tomography, and magnetic resonance imaging provide valuable atrial depictions that aid in the evaluation of the RA These imaging technologies along with observation of associated clinical symptoms of RA are key to deflecting falsepositive diagnosis and detecting missed findings [6, 7]. Several studies have suggested that right atrial engineered heart tissue, spurred by corresponding growth factors and receptor systems, could help repair an infarcted heart, though prior research has not investigated the role that local activation of RA c-Kit+ CPCs may play in healing a damaged heart [7, 8]
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