Amplification of the COX/TXS/TP receptor pathway enhances uridine diphosphate-induced contraction by advanced glycation end products in rat carotid arteries
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Advanced glycation end products (AGEs) play a pivotal role in vascular functions under various pathophysiological conditions. Although uridine diphosphate (UDP) is an important extracellular nucleotide, the relationship between AGEs and UDP regarding their effect on vascular functions remains unclear. Therefore, we investigated the effects of AGE-bovine serum albumin (AGE-BSA) on UDP-mediated responses in rat thoracic aorta and carotid arteries. In rat thoracic aorta, UDP-induced relaxation was observed and this relaxation was similar between control (1.0 v/v% PBS) and AGE-BSA-treated (0.1 mg/mL for 60 min) groups. In contrast, contraction but not relaxation was obtained following UDP application to carotid arteries with and without endothelia; contraction was greater in the AGE-BSA-treated group than in the control group. The difference in UDP-induced contraction between the two groups was not abolished by the use of a nitric oxide synthase (NOS) inhibitor, whereas it was abolished by the use of cyclooxygenase (COX), thromboxane synthase (TXS), and thromboxane-prostanoid (TP) receptor antagonist. Further, the difference in UDP-induced contraction was not abolished by the use of a cPLA2 inhibitor, whereas it was abolished by the use of an iPLA2 inhibitor. UDP increased TXA2 release in both groups, and its level was similar in both groups. Moreover, the release of PGE2, PGF2α, and PGI2 was similar among the groups. Under NOS inhibition, TP receptor agonist–induced contraction increased in the AGE-BSA-treated group (vs. control group). In conclusion, the increase in UDP-induced carotid arterial contraction by AGE-BSA can be attributed to an increase in the COX/TXS/TP receptor pathway, particularly, TP receptor signaling.
KeywordsAdvanced glycation end products Carotid arteries Contraction Thromboxane-prostanoid receptor Uridine diphosphate Vascular smooth muscle
We would like to thank Yuri Asano, Akari Ishibiki, Saya Imamura, Myu Kozakai, Kana Saegusa, Kanako Takimoto, Takeru Toda, Yuka Hayashida, Taiga Yoshida, Marina Ito, Yurika Ezaki, Amane Kurakata, Yuzuki Sato, Tamayo Hashimoto, Yurina Mae, and Hiyori Yokoyama for their excellent technical assistance. We also thank Enago (www.enago.jp) for the English language review.
T.M. and T.K. conceived and designed the research; T.M., M.K., K.T., and T.K. performed the experiments; T.M., M.K., K.T., T.K, and K.T. analyzed the data; T.M., M.K., K.T., T.K., K.T., and T.K. interpreted the results of experiments; T.M. prepared the figures; T.M. drafted the manuscript; T.M. and T.K. edited and revised the manuscript; and T.M., M.K., K.T., T.K., K.T., and T.K. approved the final version of the manuscript.
This work was supported in part by grants JSPS KAKENHI grant numbers JP18K06861 (to Takayuki Matsumoto), JP17K08318 (to Kumiko Taguchi), and JP18K06974 (to Tsuneo Kobayashi).
Compliance with ethical standards
All animal studies were conducted according to the Guiding Principles for the Care and Use of Laboratory Animals from the Committee for the Care and Use of Laboratory Animals of Hoshi University (Tokyo, Japan) (permission code: 29-086).
Conflict of interest
The authors declare that they have no conflict of interest.
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