title: H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation.
abstract: Our previous study demonstrated that angiotensin II (Ang II) upregulates the expression of Kv1.5, a promising target for atrial fibrillation (AF) therapy, by activating ROS-dependent P-Smad2/3 and P-ERK 1/2. A recent study showed that hydrogen sulfide (H2S) may modulate the effects of angiotensin II (Ang II) by inhibiting the NADPH oxidase 4 (Nox4)-ROS signaling in the heart. The present study aimed to determine whether H2S is involved in the regulation of atrial Kv1.5 via ROS-related mechanisms in AF. Cultured neonatal rat atrial myocytes and a beagle model of AF were used for this study. In the neonatal rat atrial myocytes, quantitative PCR and enzyme immunoassays revealed that the mRNA expression levels of angiotensinogen, angiotensin-converting enzyme, and Ang II type I receptor (AT1R) and the Ang II supernatant concentration were significantly increased by hydrogen peroxide (H2O2) incubation, and these H2O2-induced alterations were reversed by diphenyleneiodonium, apocynin and H2S supplementation. Flow cytometry and Western blotting revealed that blockade of H2S biosynthesis using dl-propargylglycine increased ROS production and the expression of Ang II and Kv1.5. Sodium hydrosulfide (an exogenous H2S donor) and Nox4 siRNA inhibited Ang II-induced ROS production and Ang II-induced expression of Kv1.5, P-Smad2/3, P-ERK 1/2. Sodium hydrosulfide suppressed the Ang II-induced upregulation of Nox4. In our beagle AF model, 24 h of rapid atrial pacing (RAP) increased the atrial Ang II concentration, ROS production and the protein expression of Nox4, Kv1.5, P-Smad2/3 and P-ERK 1/2. These RAP-induced changes were inhibited by H2S supplementation and losartan (an AT1R blocker) pretreatment. In conclusion, our study indicates that H2S downregulates Ang II-induced atrial Kv1.5 expression by attenuating Nox4-related ROS-triggered P-Smad2/3 and P-ERK 1/2 activation during AF. H2S supplementation would be beneficial for AF treatment via the suppression of atrial Kv1.5 expression.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Chenggui
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Tang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Juhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Qinglang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Longyun
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yesong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: hzbin2603@163.com.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: xiurengao03@163.com.
authors.forename: Xiuren
authors.initials: X
authors.lastname: Gao
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D006325:Heart Atria / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000737:chemistry*; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D008297:Male; D032342:Muscle Cells / Q000166:cytology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D009861:Onium Compounds / Q000737:chemistry; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000098:Acetophenones; D051666:Kv1.5 Potassium Channel; D009861:Onium Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C007517:diphenyleneiodonium; C056165:acetovanillone; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D006862:Hydrogen Sulfide
keywords: Angiotensin II; Atrial fibrillation; Hydrogen sulfide; Kv1.5; Reactive oxygen species