Date Published: January 19, 2017
Publisher: Public Library of Science
Author(s): Kai Cui, Yang Luan, Zhe Tang, Ke Rao, Tao Wang, Zhong Chen, Shaogang Wang, Jihong Liu, Daowen Wang, Yu Huang.
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.
Erectile dysfunction (ED), defined as an inability to attain or maintain sufficient penile erection for satisfactory sexual intercourse, is one of the most frequent conditions in andrology . ED has various etiologies, including many risk factors of vascular diseases, neurologic abnormalities, and hormonal disturbances [2,3]. Aging is one of the most common risk factors for male sexual dysfunction, and age-related ED may seriously affect the quality of life in men aged above 40 years. Previous epidemiological studies have also shown that ED was a complex disorder, with aging as an independent predictor . Recent epidemiological studies demonstrated that the prevalence of ED ranged from 2% to 9% in men aged 40–49 years, and increased to 20–40% in men aged 60–69 years, and affected almost all the men older than 70 years [5–7]. Age-related ED is difficult to treat effectively with conventional drugs , wherefore a better understanding of age-related ED is urgently needed to facilitate the development of new therapy strategies.
We previously demonstrated that the hKLK1 gene plays a preventive role in age-related ED by promoting the expression of eNOS and inhibiting corporal fibrosis . However, the detail mechanism of NOS regulation by hKLK1 is still unknown. Furthermore, although cAMP is known to be benefit in age-related ED, few studies involved its regulatory way. The current study initially demonstrated that enhancing KKS by over-expression of hKLK1 could regulate the activity of DDAH/ADMA/NOS/cGMP and the COX-2/PTGIS/cAMP pathways, which increased the production of cGMP and cAMP, resulting in improved age-related ED.
We concluded that hKLK1 plays a protective role in age-related ED. The DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP pathways were linked to the mechanism hKLK1 could increase the levels of cGMP and cAMP, which might provide novel therapy targets for age-related ED.