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 discontinuat...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.展开更多
基金Acknowledgments This work was supported by the National High Technol- ogy Research and Development Program of China （Project 2006AA02Z4B5）, the National Natural Science Foundation of China （Project 2010）, and a Key Project （9251018201002） of Guangdong Province Natural Science Foundation （to JL）. It was also supported in part by Grants HL072166, HL085629, and HL068936 of the NIH and an Established Investigator Award （0740025N） of the American Heart Association （to XW）.
文摘由 ubiquitin-proteasome 系统的细胞内部的蛋白质降级是 ATP 依赖者，和最佳的 ATP 集中激活 proteasome 在 vitro 的功能是 ~ 100 渭 M。细胞内部的 ATP 层次在在这个范围以内的水平通常在低 millimolar 范围，而是 ATP 被显示在 vitro 禁止 proteasome peptidase 活动。这里，我们报导支持在生理的层次的细胞内部的 ATP 双向地调整的一个假设的新证据 26S proteasome 在房间的解朊的功能。首先，我们证实 ATP 在 vitro 在 26S proteasome 上施加了双向规定，与最佳的 ATP 集中(在 50 和 100 渭 M 之间) 刺激 proteasome 像糜蛋白酶的活动。第二，我们发现操作细胞内部的 ATP 层次也在有教养的房间在 proteasome 特定的蛋白质底层的层次导致了双向变化。最后，测量增加提高的细胞内部的 ATP，当减少的细胞内部的 ATP 稀释了导致房间死亡的 proteasome 抑制的能力时。这些数据强烈建议在生理的集中范围以内的内长的 ATP 能在 proteasome 活动施加否定影响，允许房间到很快，在应力下面的 ATP 减小上的 upregulate proteasome 活动调节。
基金financed by grants from the National Natural Science Foundation of China(Nos.81900689 and 81870483)China Postdoctoral Science Foundation(2018M643047)
文摘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.
