Involvement of DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP Pathways in Human Tissue Kallikrein 1 Protecting Erectile Function in Aged Rats.
Involvement of DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP Pathways in Human Tissue Kallikrein 1 Protecting Erectile Function in Aged Rats.
复制标题
DDAH/ADMA/NOS/cGMP 和 COX-2/PTGIS/cAMP 通路参与人体组织激肽释放酶 1 保护老年大鼠的勃起功能
DOI：
10.1371/journal.pone.0170427
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Cui K;Luan Y;Tang Z;Rao K;Wang T;Chen Z;Wang S;Liu J;Wang D
我们之前的研究报道了人类组织激肽激酶1 （Human Tissue Kallikrein 1, hKLK1）在老龄转基因大鼠中保留了勃起功能，但没有详细报道hKLK1通过激活cGMP和cAMP保护老龄大鼠勃起功能的机制。为探讨其潜在机制，将雄性野生型Sprague-Dawley大鼠（WTR）和携带hKLK1基因的转基因大鼠（TGR）饲养至4月龄和18月龄，分为4组：幼龄WTR （yWTR）为对照，老年WTR (aWTR)，老年TGR （aTGR）和携带HOE140的老年TGR （aTGRH）。用海绵体神经电刺激法评价各组大鼠勃起功能，用大鼠海绵体内压/平均动脉压（ICP/MAP）比值测定各组大鼠勃起功能。采用western blot、免疫组化、RT-PCR检测cAMP、cGMP表达水平及相关信号通路。我们的实验结果显示，与其他两组相比，aWTR组和aTGRH组的勃起功能较低。cAMP和cGMP的表达水平也明显低于其他两组。aWTR组大鼠海肌体中DDAH/ADMA/NOS/cGMP、COX-2/PTGIS/cAMP等相关信号通路的表达也下调。我们的研究结果表明，hKLK1在年龄相关性ED中发挥保护作用，DDAH/ADMA/NOS/cGMP和COX-2/PTGIS/cAMP通路与hKLK1增加cGMP和cAMP水平的机制有关，这可能为年龄相关性ED的治疗提供新的靶点。
Our previous studies had reported that Human Tissue Kallikrein 1 (hKLK1) preserved erectile function in aged transgenic rats, while the detailed mechanism of hKLK1 protecting erectile function in aged rats through activation of cGMP and cAMP was not mentioned. To explore the latent mechanism, male wild-type Sprague-Dawley rats (WTR) and transgenic rats harboring the hKLK1 gene (TGR) were fed to 4 and 18 months old and divided into four groups: young WTR (yWTR) as the control, aged WTR (aWTR), aged TGR (aTGR) and aged TGRs with HOE140 (aTGRH). Erectile function of all rats was evaluated by cavernous nerve electrostimulation method and measured by the ratio of intracavernous pressure/ mean arterial pressure (ICP/MAP) in rats. Expression levels of cAMP and cGMP were assessed, and related signaling pathways were detected by western blot, immunohistochemistry and RT-PCR. Our experiment results showed erectile function of the aWTR group and aTGRH group was lower compared with those of other two groups. Also, expression levels of cAMP and cGMP were significantly lower than those of other two groups. Moreover, expressions of related signaling pathways including DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP were also downregulated in the corpus cavernosum of rats in aWTR group. Our finding revealed hKLK1 played a protective role in age-related ED. The DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP pathways that were linked to the mechanism hKLK1 could increase the levels of cGMP and cAMP, which might provide novel therapy targets for age-related ED.