Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.
Our results show that Ucn evokes potent positive inotropic and lusitropic effects mediated, at least in part, by an increase in I(CaL) and [Ca(2+)](i) transient amplitude. These effects may involve the activation of Epac, PKC, and MAPK signalling pathways.
Summary
1. Urocortin‐2 (Ucn2) is a vasoactive peptide belonging to the corticotrophin‐releasing factor (CRF) family that has potent cardiovascular actions. It has been suggested that Ucn2 participates in the pathophysiology of heart failure. However, little is known about the mechanisms underlying the action of Ucn2 in human coronary arteries. The aim of the present study was to assess the effects of Ucn2 on the vascular tone of human coronary arteries dissected from heart failure patients.
2. Human coronary arteries were dissected from the hearts of patients subjected to orthotopic heart transplantation. Coronary arteries were obtained from 17 patients with heart failure due to dilated cardiomyopathy of ischaemic origin in Stage III–IV of the New York Heart Association classification. Changes in tone were measured in arterial rings using force transducers.
3. Application of increasing concentrations of Ucn2 (5–20 nmol/L) to arterial rings precontracted with agonists induced dose‐dependent relaxation of the coronary artery, which was independent of endothelial cell activation. Furthermore, the inhibition of the adenylyl cyclase by MDL‐12 (100 nmol/L) and protein kinase A (PKA) by H89 (1 μmol/L) prevented Ucn2‐mediated relaxation of coronary artery rings.
4. The results of the present study suggest that, in heart failure patients, Ucn2 could be useful in modulating coronary artery circulation independent of endothelial integrity through mechanisms that involve adenylyl cyclase activation and PKA stimulation. The findings warrant further investigation of the role of Ucn2 in circulatory regulation and its potential therapeutic application in heart disease.
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