PFI-3 induces vasorelaxation with potency to reduce extracellular calcium influx in rat mesenteric artery
Jing Li,
Xue-Qi Liang,
Yun-Feng Cui,
Yu-Yang Fu,
Zi-Yue Ma,
Ying-Tao Cui,
Xian-Hui Dong,
Hai-Jun Huang,
Ting-Ting Tong,
Ya-Mei Zhu,
Ya-Dong Xue,
Yong-Zhen Wang,
Tao Ban,
Rong Huo
Affiliations
Jing Li
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Xue-Qi Liang
Department of Pharmacy, Second Affiliated Hospital of Qiqihar Medical College, Qiqihar, Heilongjiang Province, China
Yun-Feng Cui
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Yu-Yang Fu
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Zi-Yue Ma
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Ying-Tao Cui
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Xian-Hui Dong
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Hai-Jun Huang
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Ting-Ting Tong
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Ya-Mei Zhu
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Ya-Dong Xue
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Yong-Zhen Wang
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Tao Ban
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Rong Huo
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China
Background PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent cellular effects, has recently been developed. Although PFI-3 has been reported as a potential therapeutic agent targeting thrombomodulin, its role in the regulation of vascular function remains unknown. Therefore, we aimed to investigate the impact of PFI-3 on arterial vessel tone. Methods A microvascular tension measurement device (DMT) was utilized to identify alterations in vascular tension within the mesenteric artery. To detect variations in cytosolic [Ca2+]i, a Fluo-3/AM fluorescent probe and fluorescence microscope were employed. Additionally, whole-cell patch clamp techniques were utilized to evaluate the activity of L-type voltage-dependent calcium channels (VDCCs) in cultured arterial smooth muscle cells (A10 cells). Results PFI-3 exerted a dose-dependent relaxation effect on rat mesenteric arteries with both intact and denuded endothelium after phenylephrine (PE)- and high-K+-induced constriction. PFI-3-induced vasorelaxation was not affected by the presence of L-NAME/ODQ or K+ channel blockers (Gli/TEA). PFI-3 abolished Ca2+-induced contraction on endothelium-denuded mesenteric arteries preincubated by PE in Ca2+-free solution. Incubation with TG had no impact on PFI-3-induced vasorelaxation pre-contracted by PE. PFI-3 reduced Ca2+-induced contraction on endothelium-denuded mesenteric arteries pre-incubated by KCl (60 mM) in Ca2+-free solution. PFI-3 declined extracellular calcium influx in A10 cells detected by Fluo-3/AM fluorescent probe and fluorescence microscope. Furthermore, we observed that PFI-3 decreased the current densities of L-type VDCC by whole-cell patch clamp techniques. Conclusions PFI-3 blunted PE and high K+-induced vasoconstriction independent of endothelium on rat mesenteric artery. The vasodilatory effect of PFI-3 may be attributed to its inhibition of VDCCs and receptor-operated calcium channels (ROCCs) on vascular smooth muscle cells (VSMCs).
