Abstract
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.
Highlights
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 [1]
HKLK1 could restore the erectile function of aged Transgenic Rat (TGR) (aTGR) to normal level of the young wild-type SD rats (WTRs) (yWTR) group, while the protective role was abolished in the aged TGRs with HOE140 (aTGRH) group (P >0.05) (Fig 1)
We detected the expression of the Human Tissue Kallikrein 1 (hKLK1) gene in the corpus cavernosum of rats at the DNA, mRNA and protein levels, and we found that all rats in the aTGR and aTGRH groups carried the hKLK1 gene
Summary
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 [1]. 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 shown that ED was a complex disorder, with aging as an independent predictor [4]. 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 [5,6,7]. Age-related ED is difficult to treat effectively with conventional drugs [8], wherefore a better understanding of age-related ED is urgently needed to facilitate the development of new therapy strategies
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