Doxorubicin increases G-protein coupled receptor-mediated vasoconstriction in coronary arteries via the mitogen-activated protein kinase kinase 1/2 pathway

Abstract

Anthracyclines are one of the most effective chemotherapy drugs, but are associated with cardiotoxicity, including hypertension, however, little is known about the effect of anthracyclines on the vascular tone. Emerging data indicate that the anthracycline doxorubicin induces increases in vascular tone via endothelin subtype A (ET_A) and B (ET_B), serotonin (5-HT) subtype 1B (5-HT_1B), and thromboxane prostanoid (TP) G-protein coupled receptors (GPCRs) in coronary arteries. This study examined for the first time whether the mitogen-activated protein kinase kinase 1/2 (MEK 1/2) pathway is involved in the doxorubicin-induced increase of vasoconstriction. This study used an organ culture model, where left anterior descending arteries (LAD) from rats were incubated with doxorubicin (0.5 μM) in the absence and presence of the MEK 1/2 specific inhibitor U0126 (5 μM), and GPCR-mediated vasoconstriction was analysed by wire-myography. GPCR mRNA levels and GPCR expression and localisation on LAD arteries were investigated by real-time PCR and immunohistochemistry. Doxorubicin treatment increased the vasoconstriction through ET_A (278 % increase at 10^−8.5 M endothelin-1 (ET-1), 5-HT_1B (193 % increase at 10^−5.5 M 5-carboxamidotryptamine (5-CT)) and TP (32 % increase at 10^−6.5 M U46619) receptors, and decreased ET_B-mediated vasoconstriction (37 % decrease at 10^−7.5 M Sarafotoxin 6c (S6c)), however, a decrease in ET_B mRNA was detected. Co-incubation with U0126 decreased doxorubicin-mediated increased vasoconstriction through ET_A, 5-HT_1B, and TP receptors. This novel study shows that doxorubicin treatment of LAD arteries increases vasoconstriction through ET_A, 5-HT_1B, and TP receptors through the MEK 1/2 pathway.