Inhibition of LIM kinase reduces contraction and proliferation in bladder smooth muscle.

• 影响指数: 14.903
• 发表时间: Jul 2021
• 来源期刊: Acta Pharm Sin B
• DOI: 10.1016/j.apsb.2021.01.005
• PMID: 34386328
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Yu Q,Wu C,Chen Y,Li B,Wang R,Huang R,Li X,Gu D,Wang X,Duan X,Li S,Liu Y,Wu W,Hennenberg M,Zeng G

关键词: 4E-BP1, 4E-binding protein 1; ADF, actin depolymerizing factors; BOO, bladder outlet obstruction; BPH, benign prostatic hyperplasia; Bladder smooth muscle contraction; CCK-8, Cell Counting Kit-8; Cofilin phosphorylation; Ct, number of cycles; DMSO, dimethyl sulfoxide; EdU, 5-ethynyl-2′-deoxyuridine; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; H&E, hematoxylin and eosin; HBSMCs, human bladder smooth muscle cells; HRP, horseradish peroxidase; LIMK; LIMKs, LIM kinases; LUTS, lower urinary tract symptoms; Lower urinary tract symptoms (LUTS); MLC, myosin light chain; MW, molecular weight; MYPT1, myosin-binding subunit; OAB, overactive bladder; Overactive bladder (OAB); PCNA, proliferating cell nuclear antigen; RT-qPCR, reverse transcription and quantitative polymerase chain reaction; STK16, serine/threonine kinase 16; TESK1, testicular protein kinase 1; TXA2, thromboxane A2; WST-8, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt; siRNA, small interfering RNA

Abstract

Overactive bladder (OAB) is the most bothersome symptom in lower urinary tract symptoms (LUTS). Current pharmacologic treatment aims to inhibit detrusor contraction; however, shows unsatisfied efficacy and high discontinuation rate. LIM kinases (LIMKs) promote smooth muscle contraction in the prostate; however, their function in the bladder smooth muscle remains unclear. Here, we studied effects of the LIMK inhibitors on bladder smooth muscle contraction and proliferation both in vitro and in vivo experiments. Bladder expressions of LIMKs are elevated in OAB rat detrusor tissues. Two LIMK inhibitors, SR7826 and LIMKi3, inhibit contraction of human detrusor strip, and cause actin filament breakdown, as well as cell proliferation reduction in cultured human bladder smooth muscle cells (HBSMCs), paralleled by reduced cofilin phosphorylation. Silencing of LIMK1 and LIMK2 in HBSMCs resulted in breakdown of actin filaments and decreased cell proliferation. Treatment with SR7826 or LIMKi3 decreased micturition frequency and bladder detrusor hypertrophy in rats with bladder outlet obstruction. Our study suggests that LIMKs may promote contraction and proliferation in the bladder smooth muscle, which could be inhibited by small molecule LIMK inhibitors. LIMK inhibitors could be a potential therapeutic strategy for OAB- related LUTS.