|
 
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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 4
| Issue : 3 | Page : 81-86 |
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The role of microRNA in erectile dysfunction
Chunhui Liu1, Run Wang2
1 Department of Surgery, Division of Urology, McGovern Medical School, University of Texas,Texas, USA; Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
2 Department of Surgery, Division of Urology, McGovern Medical School, University of Texas; University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| Date of Web Publication | 28-Sep-2017 |
Correspondence Address:
Run Wang
Department of Surgery, Division of Urology, McGovern Medical School, University of Texas, 6431 Fannin Street, MSB 6.018, Houston, Texas 77030
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jina.jina_14_17
Erectile dysfunction (ED) is the most frequently treated sexual dysfunction in men and affects 70% of men over 70. Recently, numerous studies have focused on the pathogenesis of ED and found many causes and several key molecular changes. However, the understanding of the ED mechanism is still limited. MicroRNAs (miRNAs) are small, noncoding RNA molecules. They regulate many physiological and pathological processes, including ED. In this review, we summarize the expression and regulation mechanisms of miRNAs in ED. In ED rats and patients, many miRNAs were found increased or decreased in corpus cavernosum tissues or blood. MiRNAs can regulate erectile function by regulating many processes related to erection, such as regulating nitric oxide synthase activation, endothelial function, smooth muscle cells, and androgen function. In summary, we found that miRNAs play a critical role in ED development. However, there is inadequate direct evidence to reveal the regulatory mechanism. Further studies are required to meet the scientific needs.
Keywords: Erectile dysfunction, expression, mechanism, microRNA
How to cite this article:
Liu C, Wang R. The role of microRNA in erectile dysfunction. J Integr Nephrol Androl 2017;4:81-6 |
| Introduction | |  |
Erectile dysfunction (ED) is the most frequently treated sexual dysfunction in men. It is defined as the recurrent or consistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance.[1] The incidence rate of ED ranges from 6% to 76% in different regions and ages.[2],[3],[4] In the United States, the prevalence rate is 15% in men 40–59-year-old, 44% in men 60–69-year-old, and 70% in men over 70.[5] In China, the incidence rate of ED in age groups younger than 30, 30–39, 40–49, 50–59, 60–69, and over 70 years were 20.86%, 25.30%, 40.48%, 60.12%, 79.10%, and 93.72%, respectively.[6] ED is considered a psychogenic and organic disorder and associated with systemic diseases, such as metabolic syndrome, diabetes, cardiovascular diseases, stress, anxiety, and depression.[7] In the past 30 years, many studies focused on the pathophysiology of ED and discovered several key molecules, such as nitric oxide (NO), endothelial NO synthase (eNOS), Rho-associated protein kinase (ROCK), and transforming growth factor beta, that were involved in the development of ED.[8] With the help of NOS, the NO produces and diffuses out the tissues, then enters the smooth muscle cells and increases the cyclic guanosine monophosphate (cGMP) by binding and stimulating guanylyl cyclase. In the end, the cGMP activates protein kinase G (PKG) resulting in hyperpolarization and decreased cytoplasmic Ca 2+, causing smooth-muscle relaxation.[9],[10] The ROCK can regulate myosin phosphatase target subunit 1, resulting Ca 2+ -sensitization of the contractile proteins, enhancing smooth muscle contraction.[11] However, our understanding of ED pathogenesis is still evolving.
MicroRNAs (miRNAs) are small, noncoding RNA molecules. Their length is about 22 nucleotides.[12] More than 1000 miRNAs are now validated in human RNA.[13] It estimates that miRNAs may regulate the expression of more than 60% of human genes.[14] The biosynthesis of mature miRNAs in mammal is a complicated and multistep process [Figure 1]. First, DNA transcribes into primary miRNA with the help of RNA polymerase II.[15] Second, the primary miRNA cleaves into 70–100 nucleotides precursor miRNAs with the help of Drosha.[16] Then, the precursor miRNA is exported to the cytoplasm. Third, the precursor miRNA shears into 20–25 nucleotide double strand RNAs by Dicer in the cytoplasm.[17] In the end, the double-stranded RNA separates and one of the single-stranded RNAs is then matured, and this single-stranded RNA is the miRNA. MiRNAs can inhibit translation of target mRNA by binding to a 3' untranslated region (3'UTR). Through this regulation, miRNAs can modulate almost all physiological and pathological processes, including the development of ED.[18],[19] The purpose of this review is to summary the expression and regulation mechanisms of miRNAs related to ED. | Figure 1: The basic process of microRNA biosynthesis and mechanisms of inhibiting gene translation
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| Micrornas as Biomarkers in Erectile Dysfunction | | |
MiRNAs present as biomarkers in many diseases, including various cancers, psychiatric disorders, and immune disease.[20],[21],[22] Although there is not enough evidence showing that miRNAs can used as biomarkers in ED, different expressions of miRNAs have been identified in various types of animal models and patients [Table 1]. | Table 1: Summary of studies focusing on microRNAs expression profiling in erectile dysfunction
Click here to view |
In 2014, Pan et al. used the GeneChip array and quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression profile of miRNA in aging rats with ED. In this study, the rats were divided into three groups (n = 8 each group): Aging rats with ED, aging rats with normal erectile function, and young rats. RNA was isolated from penile tissue sample without urethra and other adventitial tissues. The GeneChip results showed 428 miRNAs dysregulated in aging rats with ED compared with aging rats with normal erectile function and normal young rats. 26 miRNAs were changed above twofold. From 10 upregulated miRNAs, four miRNAs (miR-1, miR-200a, miR-203, and miR-206) were validated by qRT-PCR. In addition, Pan et al. predicted the four miRNAs would regulate apoptosis, fibrosis, and endothelium dysfunction in the aging ED rats.[24] This result showed that these four miRNAs may paly crucial roles in the pathophysiology of aging ED.
In a later study, Pan et al. detected the miRNA expression in a murine model with type 2 diabetes mellitus-associated ED. The C57BL/KsJ-db−/db − murine was used as an ED animal model. The results showed erectile function decreased significantly in the C57BL/KsJ-db−/db − group. The GeneChip array showed that there were 1787 dysregulated miRNAs in the ED group compared with those in the control group. The qRT-PCR validated miR-122 and miR-133a decreased, and miR-206 and miR-18a increased in type two diabetic rats with ED. They predicted the four miRNAs can regulate several genes which may modulate the crucial signaling pathways of normal erection, eNOS/cGMP/PKG, PGE/cyclic adenosine monophosphate/protein kinase A, and vascular smooth muscle relaxation signaling pathways. They also confirmed insulin-like growth factor-1 (IGF-1) was the target of miRNA-18a and miR-206.[25] From this study, it appears that miRNA-18a and miR-206 can regulate type 2 diabetes mellitus-associated ED through IGF-2.
In 2015, Barbery et al. fed the 6-week-old mice a diet consisting of 60% fat for 22 weeks to build a diet-induced vasculogenic ED animal model. They found that 65 miRNAs were downregulated and five miRNAs were increased by NanoString microarray and the majority of miRNAs tended to decrease in diet-induced vasculogenic ED. In the end, they validated that miR-1937c and miR-151-5p were upregulated and miR-153 and miR-425 were downregulated by qRT-PCR.[26] This result showed that miRNAs may regulate vasculogenic ED.
Although the number of animals is limited, it is clear that miRNAs are abnormally expressed in ED. However, there is no common upregulated or downregulated miRNAs in different ED models. The reasons may be that different types of ED have its unique regulating miRNAs. It is also possible be caused by that only a small amount of miRNAs are validated in different studies, so common changes of miRNAs are not detected.
MiRNAs are stable in body fluids; they can be detected in serum, blood, and urine. Jiang et al. detected the expression of miR-93, miR-320, and miR-16 in forty diabetic patients with ED, forty diabetic patients without ED and forty healthy individuals. The results showed the expression levels of miR-93, miR-320, and miR-16 were higher in ED patients compared with other two groups. They also used the receiver operating characteristic curves to detect the diagnostic ability of miR-93, miR-320, and miR-16. The results indicated that miR-93, miR-320, and miR-16 had a diagnostic value in diabetic ED.[27]
| The Mechanism of Microrna in Erectile Dysfunction | | |
Penile erection is a complex neurovascular event. During the erection process, sexual stimulation results in relaxation of smooth muscle cells and increase of blood inflow. The increasing blood inflow fills the lacunar spaces in the corpora cavernosa and compresses the subtunical venules, thereby blocking the venous outflow, which maintains the erection. Erection is not only controlled by central and peripheral nervous systems but also depends on the integrity of vascular endothelium and penile cellular components as well as the interaction of hormonal factors.[28] Multiple molecular pathways are found to be involved in this process. The most important and widely recognized mechanism is the NO/cGMP pathway.[8] Any abnormality involving these pathways can lead to ED. Recent studies showed that miRNAs can regulate almost all steps related to erectile function [Figure 2].
MicroRNAs inhibit nitric oxide synthase activation
NO is the primary neurotransmitter involved in penile erection.[29] It actives guanylyl cyclase and results in increased intracellular cGMP in smooth muscle cells. The cGMP then activates a number of signaling cascades, which finally results in smooth muscle relaxation and blood inflow.[28] There is a consensus that NO is synthesized from L-arginine by three different isoforms of NOS: neuronal NOS, inducible NOS (iNOS), and eNOS.[30] Neuronal NOS produces neural NO which is responsible for initial vasodilation, and eNOS produces endothelial NO which contributes to the maintenance of the erection.[31] Recent research studies revealed that miRNAs expression is related to NOS expression. For example, miR-27b and eNOS showed opposite expression levels in the corpus cavernosum of rats with chronic alcoholism and diabetes mellitus.[32] In addition, reduction of miR-221 and miR-222 in human endothelial cells increased eNOS mRNA levels.[33] The mechanism of miRNAs regulating NOS expression can divide into the direct and indirect regulating. MiRNAs binding with NOS mRNA and inhibiting NOS expression is direct regulating, such as miR-155 can directly inhibit eNOS expression.[34] MiR-939 and miR-26a can directly inhibit iNOS expression.[23] Besides direct regulating, miRNA can regulate some genes which can regulate NOS expression, such as miR-146a can inhibit iNOS expression by directly targeting tumor necrosis factor receptor-associated factor 6.[35]
MicroRNA regulate endothelial function
The penis is a highly vascularized organ. Vasculogenic factors are the most common etiology of organic ED mostly involved in endothelial cell dysfunction. Endothelium plays an important role in erection by regulating a series of biological events, including regulating smooth muscle cell contraction and relaxation, maintenance of vascular pressure, thrombosis, and platelet aggregation inhibition.[36] Recently, miRNAs were suggested to be important regulators of endothelial cell function. First, miRNAs can regulate the apoptosis of endothelial cells. Apoptosis is a process of programmed cell death.[37] In ED patients, the apoptosis was found to be increased in penile endothelial cells.[38] In aging rats with ED, miR-1 and miR-203 were found to regulate endothelial cell apoptosis by inhibiting AKT3 and PIK3CA.[24] Second, miRNAs can regulate endothelial aging. In aged rats with ED, miR-200a was found to regulate endothelial aging through a silent information regulator 1 (SIRT1).[39] SIRT1 is a nicotinamide adenine dinucleotide NAD +-dependent deacetylase which regulates aging and metabolic disorders.[40] Besides miR-220a, there are still other miRNAs that can regulate SIRT1 expression in endothelial cells, such as miR-217, miR-34a, miR-22, and miR-195.[41],[42] However, the abnormal expression and dysregulation of those miRNAs have not been directly proven in penile endothelial cells at present time. MiRNAs can also regulate endothelial cell proliferation and migration. For example, miR-126 can suppress the Notch1 inhibitor delta-like one homolog and lead to endothelial proliferation after an injury.[43] MiR-152 can directly target ADAM metallopeptidase domain 17, inhibiting proliferation and migration in human umbilical cord vein endothelial cells.[44] Along with direct regulation, miR-150 can also serve as signaling molecules mediating intercellular communication to regulate migration.[45]
MicroRNAs regulate smooth muscle cells
Smooth muscle cells are the main composition constituting the blood vessel wall. Its relaxation can promote cavernous sinusoidal dilation and arterial blood inflow and lead to penile erection.[46] Alteration of smooth muscle structure and function in the corpus cavernosum can cause ED.[47] For example, smooth muscle cells' decrease is closely related to ED.[48] The aberrant expressed miRNAs found in ED can regulate smooth muscle structure and function. In diet-induced vasculogenic ED, miR-145 was one of the most abundantly expressed miRNAs in a high-throughput screening.[26] It has been used as a smooth muscle cell marker.[49] Research has found that it can regulate vascular smooth muscle cells proliferation by inhibiting CD 40 and regulate smooth muscle cell proliferation and differentiation by binding to Klf4 in vitro.[50],[51] Besides miR-145, miR-133a and mir-206 can also regulate smooth muscle cell proliferation.[52],[53] More than regulating the proliferation and differentiation, miRNA can directly regulate the relaxation and contraction of smooth muscle cells. For example, in aged rats, miR-206 may target KCNMB2, a gene encoding the potassium channel in the smooth muscle cell membrane, and affect the process of smooth muscle relaxation.[24]
MicroRNAs regulate androgen function
Androgens play important parts in enhancing sexual desire and maintaining adequate sleep-related erections.[54] They have roles of maintenance of penile tissue structural and nerve fiber network integrity, signaling pathways in the corpora cavernosa, physiological penile response to stimuli, and penile trabecular smooth muscle growth and function.[55] Although there is no direct evidence showing how miRNAs regulate androgen-dependent erectile function, there is research demonstrating that miRNAs can regulate androgen functions in other diseases, such as in prostate cancer. MiR-30b-3p and miR-30d-5p can directly inhibit androgen receptor expression by binding to its 3'-UTR.[56]
| Conclusion | | |
Current evidence supports that miRNAs play a critical role in ED development. MiRNAs appear to be involved in NOs activation, regulation of endothelial and smooth muscle function, and androgen-dependent erection function. However, direct evidence is needed to reveal the detailed regulatory mechanisms. These researches may enable the discovery of future novel therapeutic targets.
Acknowledgment
We would like to thank Dorothy Stradinger for her editorial assistance.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1]
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