Inhibition of LIM kinase reduces contraction and proliferation in bladder smooth muscle.
Inhibition of LIM kinase reduces contraction and proliferation in bladder smooth muscle.
复制标题
抑制 LIM 激酶可减少膀胱平滑肌的收缩和增殖
DOI：
10.1016/j.apsb.2021.01.005
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Zeng G
中科院分区：
文献类型：
--
作者：
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
膀胱过度活动症(OAB)是下尿路症状(LUTS)中最令人困扰的症状。目前的药物治疗旨在抑制逼尿肌收缩，但疗效不佳，停药率高。LIM激酶(LIMK)促进前列腺的平滑肌收缩；然而，它们在膀胱平滑肌中的作用尚不清楚。在此，我们在体外和体内实验中研究了LIMK抑制剂对膀胱平滑肌收缩和增殖的影响。LIMKs在OAB大鼠逼尿肌组织中的表达升高。两种LIMK抑制剂SR7826和LIMKi3可抑制人逼尿肌条的收缩，并导致培养的人膀胱平滑肌细胞(HBSMCs)肌动蛋白细丝断裂和细胞增殖减少，同时伴随着Cofilin磷酸化的减少。在HBSMC中沉默LIMK1和LIMK2导致肌动蛋白细丝断裂和细胞增殖下降。SR7826或LIMKi3治疗可减少膀胱出口梗阻大鼠的排尿次数和膀胱逼尿肌肥大。我们的研究表明，LIMKs可能促进膀胱平滑肌的收缩和增殖，而小分子LIMK抑制剂可能抑制这一作用。LIMK抑制剂可能成为治疗OAB相关LUTS的一种潜在策略。LIM激酶(LIMK)可促进膀胱平滑肌的收缩和增殖。LIMK抑制剂可能成为治疗膀胱过度活动症相关下尿路症状的潜在策略。
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. LIM kinases (LIMKs) may promote contraction and proliferation in the bladder smooth muscle. LIMK inhibitors could be a potential therapeutic strategy for overactive bladder -related lower urinary tract symptoms.
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