Department of Urology, Ludwig Maximilian University of Munich, Munich, Germany.
Br J Pharmacol. 2018 Jun;175(11):2077-2096. doi: 10.1111/bph.14201. Epub 2018 Apr 29.
In men with benign prostatic hyperplasia, increased smooth muscle tone in the prostate may lead to bladder outlet obstruction and subsequent lower urinary tract symptoms. Consequently, medical treatment aims to inhibit prostate smooth muscle contraction. However, the efficacy of the treatment options available is limited, and improved understanding of mechanisms of prostate smooth muscle contraction and identification of new targets for medical intervention are mandatory. Several studies suggest that LIM kinases (LIMKs) promote smooth muscle contraction; however, this has not yet been examined. Here, we studied effects of the LIMK inhibitors on prostate smooth muscle contraction.
Human prostate tissues were obtained from radical prostatectomy. Phosphorylation of cofilin, a LIMK substrate, was examined using a phospho-specific antibody. Smooth muscle contractions were studied in organ bath experiments.
Real-time PCR, Western blot and immunofluorescence suggested LIMKs are expressed in smooth muscle cells of prostate tissues. Two different LIMK inhibitors, SR7826 (1 μM) and LIMKi3 (1 μM), inhibited contractions of prostate strips, which were induced by electrical field stimulation, α -adrenoceptor agonists phenylephrine and methoxamine and the TXA analogue, U46619. LIMK inhibition in prostate tissues and cultured stromal cells (WPMY-1) was confirmed by cofilin phosphorylation, which was reduced by SR7826 and LIMKi3. In WPMY-1 cells, SR7826 and LIMKi3 caused breakdown of actin filaments and reduced viability.
Smooth muscle tone in the hyperplastic human prostate may underlie the effects of LIMKs, which promote contraction. Contraction of prostate strips can be inhibited by small molecule LIMK inhibitors.
在患有良性前列腺增生的男性中，前列腺平滑肌张力增加可能导致膀胱出口梗阻和随后的下尿路症状。因此，医学治疗旨在抑制前列腺平滑肌收缩。然而，现有治疗选择的疗效有限，需要深入了解前列腺平滑肌收缩的机制，并确定新的医学干预靶点。几项研究表明 LIM 激酶（LIMKs）促进平滑肌收缩；然而，这尚未得到检验。在这里，我们研究了 LIMK 抑制剂对前列腺平滑肌收缩的影响。
从根治性前列腺切除术获得人前列腺组织。使用磷酸化特异性抗体检测 cofilin 的磷酸化，cofilin 是 LIMK 的底物。在器官浴实验中研究平滑肌收缩。
实时 PCR、Western blot 和免疫荧光表明 LIMKs 在前列腺组织的平滑肌细胞中表达。两种不同的 LIMK 抑制剂，SR7826（1 μM）和 LIMKi3（1 μM），抑制了由电场刺激、α-肾上腺素能激动剂苯肾上腺素和甲氧胺以及 TXA 类似物 U46619 诱导的前列腺条带的收缩。SR7826 和 LIMKi3 通过降低 cofilin 磷酸化来确认前列腺组织和培养的基质细胞（WPMY-1）中的 LIMK 抑制作用。在 WPMY-1 细胞中，SR7826 和 LIMKi3 导致肌动蛋白丝的分解并降低细胞活力。
增生前列腺中的平滑肌张力可能是 LIMKs 促进收缩的基础。小分子 LIMK 抑制剂可抑制前列腺条带的收缩。
