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Int. J. Mol. Sci. 2013, 14(10), 21071-21086; doi:10.3390/ijms141021071
Published: 21 October 2013
Abstract: According to the World Health Organization, infertility, associated with metabolic syndrome, has become a global issue with a 10%–20% incidence worldwide. An accumulating body of evidence has shown that the renin–angiotensin system is involved in the fertility problems observed in some populations. Moreover, alterations in the expression of angiotensin-converting enzyme-1, angiotensin-converting enzyme-2, and angiotensin-converting enzyme-3 might be one of the most important mechanisms underlying both female and male infertility. However, as a pseudogene in humans, further studies are needed to explore whether the abnormal angiotensin-converting enzyme-3 gene could result in the problems of human reproduction. In this review, the relationship between angiotensin-converting enzymes and fertile ability is summarized, and a new procedure for the treatment of infertility is discussed.
Over the past two decades, there has been a striking increase in the number of people with metabolic syndrome (MetS) worldwide. MetS is a highly prevalent condition currently considered to be a constellation of metabolic abnormalities, including blood pressure elevation, abdominal obesity, impaired glucose metabolism and hyperglycemia associated with insulin resistance (IR) [1–3]. Recently, studies have demonstrated that reproductive pathological conditions are associated with MetS, such as polycystic ovarian syndrome (PCOS), hypogonadism and erectile dysfunction [1–5]. It was estimated that approcimately 9% of the world’s reproductive population, which corresponds to 72.4 million couples, experience fertility problems . In women, ovulation disorders prevail across different races [7,8]. Polycystic ovary, which is the leading cause of anovulatory infertility, affects 5%–7% of women of reproductive age . Evidence of enhanced renin–angiotensin system (RAS) activity in PCOS suggests an important correlation between the RAS and PCOS [10,11]. Studies on the expression of angiotensin-converting enzyme-1 (ACE1) and angiotensin-converting enzyme-2 (ACE2) in male infertility cases have been reported, and Ace1−/− male mice have been found to be sterile . Despite the sperm motility and fusing location of eggs generated in Ace2−/− and Ace3−/− mice, the male mice were slightly abnormal, and both knockouts proved to be fertile [13,14]. The abovementioned facts indicate that ACE1, ACE2, and angiotensin-converting enzyme-3 (ACE3) appear to be one of the possible mechanisms responsible for infertility. Furthermore, the ACE1 has become a promising target for the treatment of MetS, which increases the risk factors of infertility, such as obesity, IR and so on [15–17]. Some studies further pointed out that ACE1 inhibitors (ACEIs) have become first-line drugs for some fertile issues [18,19]. This review attempts to summarize and explore the relationship between the sterility and ACEs expression in the ovaries and testes.
2. Renin–Angiotensin System (RAS)
It is well acknowledged that the traditional RAS contains a system of finely tuned agonists and antagonists that balance blood pressure . In recent years, attention has been focused on the physiological and pathophysiological studies of the human reproductive tract RAS. Classic components of the RAS have also been identified in the reproductive system, including in oocytes, granular cells, sperm cells, and Leydig cells [21,22]. Furthermore, the local RAS pathways, which are involved in reproductive events, have also been elucidated (Figure 1). ACE1, a key enzyme in the RAS, converts angiotensin I (AngI) into angiotensin II (AngII), which participates in female reproductive physiology via the AngII type 1 receptor (AT1R) and the AngII type 2 receptor (AT2R). In contrast, the functions of AngII in male reproductive events are stimulated by the AngII type 1 receptor (AT1R). ACE2, a homolog of ACE1, also emerges as a key factor in the regulation of the female and male reproductive performance that is mediated by angiotensin-(1–7) [Ang-(1–7)] [23–25]. Ang-(1–7), which is produced by ACE2, functions through the G protein-coupled receptor Mas [26,27]. To date, studies suggest that ACE3 might function in the testes of mice, rats, cows, and dogs, although ACE3 is not expressed in humans . Collectively, the correct balance among the ACE1/AngII/AT1R, ACE1/AngII/AT2R and ACE2/Ang-(1–7)/Mas receptor (MasR) pathways is significant in female reproductive events, particularly follicle development, granulose-lutein (GL) cell apoptosis, ovulation, and the ACE2/Ang-(1–7)/Mas receptor axis [23,29–32]. In contrast, the ACE1/AngII/AT1R and the ACE2/Ang-(1–7)/Mas receptor pathways are involved in male fertile health, particularly steroidogenesis, epididymal contractility, and sperm cell function [21,26,33,34].
ACE1 is well recognized not only for its pivotal regulatory activities in cardiovascular homeostasis , but also for its influence on fertility. There are two distinct isoforms of ACE1: somatic ACE1 (sACE1) and germinal or testicular ACE1 (tACE1). These isoforms are transcribed from the same gene through the action of alternative promoters [36,37]. It has been determined that ACE1, which is a seminal fluid protein (SFP), protects sperm during and after transfer to females . In females, ACE1 regulates the angiogenesis of ovarian endothelium and follicular growth; in contrast, in males, the sperm-migrating capability and binding ability to the zona pellucida (ZP) are affected by tACE1 . Studies further demonstrate that only tAce1-knockout male mice are sterile, whereas sAce1-deficient male mice are fertile . Moreover, sACE1 has been found to regularly express in human germ cells during fetal development, indicating that sACE1 may play a role in human germ cell development and ontogenesis [41–43].
The ACE2 gene, which was recently cloned, has an expression pattern that is restricted to endothelial cells in the heart and kidney, epithelial cells in the distal tubule of the kidney, and adult Leydig cells in the testis [36,44]. The full-length human ACE2 cDNA predicts an endothelium-bound carboxypeptidase of 805 amino acids, which has 42% homology with the N-terminal catalytic domain of ACE1 (Figure 2) and contains the following two domains: an amino-terminal catalytic domain and a carboxy-terminal domain . The expression of ACE2 in the ovaries and testes suggests that this enzyme plays a regulatory role in steroidogenesis and thus affects germ cells and reproductive health.
In 2007, Rella et al. characterized the ACE3 gene . Unlike ACE1 and ACE2, ACE3 is not widely distributed. According to available data, ACE3 is only detected in the heart, testes, and embryos. ACE3 is expressed in mice, rats, cows, and dogs and lacks catalytic activity. Investigators attribute this lack of catalytic activity to a Gln substitution for the catalytic Glu in the putative zinc-binding motif. In humans, ACE3 contains a typical zinc-binding motif (HEMGH) that is similar to that of ACE1. However, no evidence was found that the ACE3 gene is expressed, indicating that ACE3 is a pseudogene in humans . Inoue and colleagues identified ACE3 as an IZUMO1-interacting protein in mouse sperm . Through immunofluorescent staining, ACE3 was found to be located in the acrosomal cap area of fresh mouse sperm. After the acrosome reaction, ACE3 unexpectedly disappeared, and IZUMO1 remained in the sperm. IZUMO1 is considered the only sperm protein that has been proven to be essential for sperm–egg fusion.
3. Ovary ACEs
3.1. Ovary ACE1
In the 1980s, ACE1 was observed to be mostly expressed in large follicles in the ovaries. Immunoelectron microscopy analyses showed that ACE1 was distributed on the surface of follicular oocytes in a diffuse pattern and in the zona pellucida, which indicates its regulation during follicular development and oocyte maturation . The intrafollicular injection of ACE1-forming AngII was found to prevent the expected atresia in the second-largest follicle, and these results imply that AngII plays a role in the regulation of follicular growth . However, AngII, which is predominantly found in granulosa cells, is also involved in the development of atresia through the local induction of an increase in the follicular fluid androgen-to-estrogen ratio . Furthermore, AngII is part of the intraovarian paracrine or autocrine control mechanism that takes place during the ovulatory process in the ovaries of pigs, rabbits, and cattle [49,50]. This effect may occur via AT2R because its specific antagonist, PD123319, reduces the AngII-induced ovulation . The aforementioned facts imply that ACE1 indirectly influences the AngII-mediated development of follicles and ovulation. Another potential mechanism for the involvement of ACE1 in female fertility involves increased oxidative stress. It is well noted that reactive oxygen species can impair the pathophysiology of human reproduction [52–55]. One of the most important consequences of increased oxidative stress is the development of an inflammatory reaction. AngII has been reported to promote oxidative stress and to exert a pro-inflammatory effect through the activation of AT1R [56,57]. Thus, increased levels of ACE1, which produce excessive AngII, might damage the reproductive ability due to increased oxidative stress. However, captopril, which is an ACE1 inhibitor, does not affect ovulation in rats and rabbits, which suggests that the ACE1/AngII/angiotensin receptor pathway is not the only pathway that regulates ovulation and induces inflammation. Other pathways, such as the ACE2/Ang-(1–7)/Mas pathway, must therefore exist [58,59].
3.2. Ovary ACE2
Increasing data have demonstrated that ACE2 is present in human and rat ovaries [26,32]. The Ang-(1–7) peptides, which are produced by ACE2, are also located in several ovarian compartments and may be quantified in follicular fluid (FF) . Gonadotropin induces changes in the ovarian expression of ACE2, Ang-(1–7), and the Mas receptor, which implies that ACE2 participates in ovarian physiology mediated by Ang-(1–7) . Moreover, in addition to AngII, Ang-(1–7) has emerged as a key factor in the control of follicle deviation . Ang-(1–7) and Mas, which are present in theca-interstitial cells, are able to stimulate ovarian steroidogenesis and thus modulate the ovarian physiological functions, such as follicular development, steroidogenesis, oocyte maturation, ovulation, and atresia . The ACE2/Ang-(1–7)/Mas axis was recently verified to promote meiotic resumption, which is highly regulated by luteinizing hormone, likely as a gonadotrophin intermediate .
4. Testis ACEs
4.1. Testis ACE1
In the early 1980s, tACE1 was found to be absent in immature rats; however, this enzyme has been shown to develop with puberty, which indicates that its expression is under hormonal control . Studies further show that tACE1 is exclusively expressed in developing spermatids and mature spermatozoa and it is localized in spermatid heads, residual bodies, and the cytoplasmic droplets of epididymal sperm [63,64]. Although tACE1 mRNA was found in spermatocytes, tACE1 protein was first present in post-meiotic step 3 spermatids and increased rapidly during further differentiation . Nikolaeva et al. developed a very quantitative assay of tACE1 expression on human spermatozoa . During the different phases of fertilization, the level of tACE1 expression on the sperm surface differed, which can dictate its role on reproduction. Therefore, it might be a new and useful tool for us to understand the roles of tACE1 and assess the reproductive ability. Moreover, the ACE1 found in seminal plasma is secreted or sloughed off from the prostate and epididymis . Ace1−/− mice exhibit impaired male fertility, and this impairment is rescued by the introduction of tACE1 into germ cells, which suggests that tACE1 plays a crucial role in male reproduction .
Many studies have reported the implication of tACE1 in capacitation. Mammalian spermatozoa must undergo a maturation process known as capacitation and a morphological change called an acrosome reaction before successful fertilization. During capacitation, sperm membranes are modified by the epididymal proteins located on their surface, and this is a crucial step to ensure successful sperm–egg interactions [67,68]. During epididymal passage, ACE1 minimizes the sperm motility by mediating the translocation of ADAM3 (Figure 2) . ADAM family members, including a disintegrin and a metalloprotease, are required for normal mouse fertility . Under capacitation conditions, evidence demonstrates that ACE1 is released from human spermatozoa in vitro and that this release is independent of the acrosome reaction [42,71]. Before binding to an egg ZP, spermatozoa adhere to the oviduct epithelium. Adherent spermatozoa may be released through the membrane tACE1. A portion of tACE1 is released from spermatozoa during capacitation, whereas other portions of tACE1 may be released during the sperm passage up the female reproductive tract to increase its binding capacity to the ZP . In addition to its important role in capacitation, tACE1 has also been shown to participate in egg–sperm fusion. It was recently reported that tACE1 exhibits glycosylphosphatidylinositol (GPI)-anchored protein releasing activity (GPIase activity), and that this activity is identical to that of phosphatidylinositol-specific phospholipase (PI-PLC). Previous studies have demonstrated that the egg-binding deficiency of Ace1-knockout sperm can be rescued by peptidase-inactivated (inactivate the ability to cleave small peptides, such as AngI and Ang II) mutant ACE1 and PI-PLC, which implies that tACE1 plays a crucial role in fertilization through this activity [73,74]. However, many reports argued that the ACE1 does not possess considerable GPIase activity [75,76]. Leisle et al.  used multiple species of sACE1, porcine brush-border membrane and MDCK cells, while Kondoh et al.  utilized tACE1, HEK293 cells and Hela cells. And the differences between the studies of Fuchs et al.  and Kondoh et al.  might own to other intracellular factors with GPIase activity. Kondoh and colleagues further demonstrated that a set of glycans modulate the GPIase activity of ACE1 .
4.2. Testis ACE2
In the male reproductive tract, ACE2 is selectively expressed by adult Leydig cells in the testis. In addition, the ACE2-producing Ang-(1–7) and its receptor Mas have also been detected in the testis, and these are mainly located in the interstitial compartment and cytoplasm of the Leydig cells . Reis et al. further demonstrated the strong influence of ACE2 in the male reproductive system by showing that humans with severe spermatogenesis impairment have lower levels of ACE2, Ang-(1–7), and Mas compared with fertile subjects . Because the sex steroid hormone is one of the major products secreted from Leydig cells, it is suggested that ACE2 participates in the modulation of spermatogenesis. In contrast to Ace1−/− male mice, which display significantly reduced fertility, both male and female Ace2-null mice are fertile , which suggests that the rescue mechanisms may be regulated by other reproduction-related proteins in the testis, such as tACE1 and ACE3. Moreover, there is evidence that the testis weight is markedly reduced in Mas-deficient mice . Therefore, substantial evidence implies that ACE2 regulates spermatogenesis.
4.3. Testis ACE3
Similarly to tACE1, tACE3 is an IZUMO1-associated protein (Figure 2). IZUMO1, which is a novel sperm-specific protein with essential factors, is located in sperm–egg fusions in mice. Izumo−/− males are infertile despite their normal mating behavior, ejaculation, and sperm motility . However, Ace3−/− mice are healthy and fertile and exhibit only slight mislocalization of IZUMO1-positive sperm compare with control mice . These results suggest that the characteristic binding nature of tACE3 to IZUMO1 is not required for the fertilization of eggs by sperm.
5. Sterility of MetS
Besides the impaired glucose metabolism, dyslipidaemia and hypertension of MetS, sterility of women and men is also associated with MetS. In females, an aberrant ovarian RAS can result in the development of several gynecological diseases such as PCOS, the patients of which are more vulnerable to MetS . PCOS is an ovulation disorder that causes impaired fecundity in females. Genetic studies further demonstrate that polymorphisms in Ace1 are related to the risk factors for PCOS. Jia and his team proposed that Ace1 insertion/deletion (I/D) polymorphisms are associated with an increased risk for PCOS . The D allele, which is found in approximately 55% of the population, is associated with increased ACE1 activity . A study further proposed that the Ace1 DD genotype is related to increased IR in women with PCOS [83,84]. Moreover, PCOS is a common and complex disease with common features of hyperinsulinemia and IR. In addition to its effect on obesity and diabetes, abnormal insulin signaling has been linked to adverse pregnancy outcomes because it affects the female hypothalamic–pituitary–gonadal axis . Accordingly, insulin-sensitizing drugs appear to enhance spontaneous ovulation and pregnancy rates .
In males, hypogonadism, erectile dysfunction and psychological disturbances are also often comorbid with MetS [1,2]. Several studies point to an increased likelihood of sperm disorders (oligozoospermia or azoospermia) and male infertility among overweight men [87,88]. Riera-Fortuny et al. found that type and grade of obesity correlated with the genotypes of the ACE1 gene I/D polymorphism in subjects with coronary heart disease of MetS . There is a significant correlation between hypertension, with more fragmented/abnormal sperm DNA, which is hypothesized that hypertension altered vascular status by enhancing reactive oxygen species (ROS) generation and limited antioxidant defence within the testes [90,91]. Furthermore, the levels of ROS are under the regulation of ACE1 and ACE2, activated by ACE1and attenuated by ACE2 [92,93].
6. Therapy for Infertility
Drugs inhibiting the RAS have shown benefits against multiple components of the MetS, indirectly ameliorate the reproductive health. Accumulating data indicate that ACE1 is a potential contributor to IR, which plays a crucial role in the pathogenesis of PCOS. Thus, treatment with the ACEI temocapril has been employed for females with IR, and this treatment improves their insulin sensitivity, which results in a favorable maternal and fetal outcome [19,94]. IR and hyperinsulinemia are implicated in the infertility of obese patients. In response to the stimulation of insulin, the serum levels of androgens are increased, and the synthesis of sex hormone binding-globulin (SHBG), which is the carrier protein for sex steroid hormones, decreases. In addition, adipose tissues store an excess amount of sex steroids, which could raise the plasma levels of androgens. The above mechanisms might lead to female infertility by impairing the ovulatory capacity of the ovaries . Because ACEIs reduced the level of AngII, these drugs might downregulate insulin sensitivity not only by altering the insulin signaling pathways but also by diminishing the blood flow to muscles [96,97].
Despite the controversial study results, there are data supporting the use of ACEIs as effective drugs for the management of infertile men with idiopathic oligospermia, because of its beneficial effect on the sperm number, motility and morphology [18,98]. ACEIs exert beneficial effects on the sperm quantity and quality by blocking the conversion of bradykinin in the related kallikrein–kinin system into inactive peptides . The accumulated bradykinin activates Sertoli cell function, regulates spermatogenesis, and leads to the maturation of spermatozoa . However, some previous studies have not found any great improvement in the sperm quantity and quality after treatment with ACEIs, partially if a different dose of ACEIs is used .
To date, all of the drugs that target the RAS, including ACEIs and antagonists of angiotensin receptors, aim to decrease the RAS function. ACE2 may serve as a novel therapeutic component of the RAS that, if activated, could treat hypertension, IR and obesity of the MetS and other relative comorbid disease, such as infertility. A further understanding of the relationship between the ACEs and the sterility with or without MetS at specific cells may be an effective single therapy against infertility. In addition, dietary manipulations and sustainable strategies for weight loss benefit body composition and improve insulin regulation, which may ultimately treat specific features of MetS and improve the fertility.
As shown in this review, infertility is associated with MetS, risk factors of which might impair the reproduction. Moreover, there is no doubt that ACE1 and ACE2 have gained recognition as significant regulators of the physiology and pathology of the reproductive system. The sperm–egg fusion process is associated with the ADAMs-associated protein ACE1 and IZUMO1-interacting protein ACE3. However, the fertility of Ace1/Ace2, Ace1/Ace3, and Ace2/Ace3 double mutants has not been addressed. If these double-mutant mouse models are generated, the association between ACEs and the cause of infertility could be elucidated more clearly. Moreover, ACEIs have become first-line drugs for the management of PCOS-related IR in infertile females and idiopathic oligozoosperm in males, although some controversial results have been observed. Thus, the aforementioned findings require confirmation in larger multicenter studies.
This work was supported by the National Basic Research Program of China (No. 2012CB944 901); the National Natural Science Program of China (No. 81070532; No. 81070541); Natural Science Program of Zhejiang Province, China (No.Y2100822); and Zhejiang Provincial Natural Science Foundation of China (No. LZ13H040001).
Conflicts of Interest
The authors declare no conflict of interest.
- Corona, G.; Rastrelli, G.; Morelli, A.; Vignozzi, L.; Mannucci, E.; Maggi, M. Hypogonadism and metabolic syndrome. J. Endocrinol. Invest 2011, 34, 557–567.
- Corona, G.; Rastrelli, G.; Vignozzi, L.; Mannucci, E.; Maggi, M. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract. Res. Clin. Endocrinol. Metab 2011, 25, 337–353.
- Lotti, F.; Corona, G.; Degli Innocenti, S.; Filimberti, E.; Scognamiglio, V.; Vignozzi, L.; Forti, G.; Maggi, M. Seminal, ultrasound and psychobiological parameters correlate with metabolic syndrome in male members of infertile couples. Andrology 2013, 1, 229–239.
- Orio, F.; Palomba, S.; Di Biase, S.; Colao, A.; Tauchmanova, L.; Savastano, S.; Labella, D.; Russo, T.; Zullo, F.; Lombardi, G. Homocysteine levels and C677T polymorphism of methylenetetrahydrofolate reductase in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab 2003, 88, 673–679.
- Unsal, T.; Konac, E.; Yesilkaya, E.; Yilmaz, A.; Bideci, A.; Onen, H.I.; Cinaz, P.; Menevse, A. Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome. J. Assist. Reprod Genet 2009, 26, 205–216.
- Boivin, J.; Bunting, L.; Collins, J.A.; Nygren, K.G. International estimates of infertility prevalence and treatment-seeking: Potential need and demand for infertility medical care. Hum. Reprod 2007, 22, 1506–1512.
- Farhi, J.; Ben-Haroush, A. Distribution of causes of infertility in patients attending primary fertility clinics in Israel. Isr. Med. Assoc. J 2011, 13, 51–54.
- Dorjpurev, U.; Kuwahara, A.; Yano, Y.; Taniguchi, T.; Yamamoto, Y.; Suto, A.; Tanaka, Y.; Matsuzaki, T.; Yasui, T.; Irahara, M. Effect of semen characteristics on pregnancy rate following intrauterine insemination. J. Med. Invest 2011, 58, 127–133.
- Azziz, R.; Marin, C.; Hoq, L.; Badamgarav, E.; Song, P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J. Clin. Endocrinol. Metab 2005, 90, 4650–4658.
- Wu, X.; Lu, K.; Su, Y. Renin-angiotensin system: Involvement in polycystic ovarian syndrome. Zhonghua Fu Chan Ke Za Zhi 1997, 32, 428–431.
- Arefi, S.; Mottaghi, S.; Sharifi, A.M. Studying the correlation of renin-angiotensin-system (RAS) components and insulin resistance in polycystic ovary syndrome (PCOs). Gynecol. Endocrinol 2013, 29, 1–4.
- Kessler, S.P.; Rowe, T.M.; Gomos, J.B.; Kessler, P.M.; Sen, G.C. Physiological non-equivalence of the two isoforms of angiotensin-converting enzyme. J. Biol. Chem 2000, 275, 26259–26264.
- Crackower, M.A.; Sarao, R.; Oudit, G.Y.; Yagil, C.; Kozieradzki, I.; Scanga, S.E.; Oliveira-dos-Santos, A.J.; da Costa, J.; Zhang, L.; Pei, Y. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002, 417, 822–828.
- Inoue, N.; Kasahara, T.; Ikawa, M.; Okabe, M. Identification and disruption of sperm-specific angiotensin converting enzyme-3 (ACE3) in mouse. PLoS One 2010, 5, e10301.
- De Kloet, A.D.; Krause, E.G.; Kim, D.-H.; Sakai, R.R.; Seeley, R.J.; Woods, S.C. The effect of angiotensin-converting enzyme inhibition using captopril on energy balance and glucose homeostasis. Endocrinology 2009, 150, 4114–4123.
- Jayasooriya, A.P.; Mathai, M.L.; Walker, L.L.; Begg, D.P.; Denton, D.A.; Cameron-Smith, D.; Egan, G.F.; McKinley, M.J.; Rodger, P.D.; Sinclair, A.J. Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. Proc. Natl. Acad. Sci. USA 2008, 105, 6531–6536.
- De Kloet, A.D.; Krause, E.G.; Woods, S.C. The renin angiotensin system and the metabolic syndrome. Physiol. Behav 2010, 100, 525–534.
- Mbah, A.; Ndukwu, G.; Ghasi, S.; Shu, E.; Ozoemena, F.; Mbah, J.; Onodugo, O.; Ejim, E.; Eze, M.; Nkwo, P. Low-dose lisinopril in normotensive men with idiopathic oligospermia and infertility: A 5-year randomized, controlled, crossover pilot study. Clin. Pharmacol. Ther 2012, 91, 582–589.
- Shiuchi, T.; Cui, T.-X.; Wu, L.; Nakagami, H.; Takeda-Matsubara, Y.; Iwai, M.; Horiuchi, M. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension 2002, 40, 329–334.
- Carey, R.M.; Siragy, H.M. Newly recognized components of the renin-angiotensin system: Potential roles in cardiovascular and renal regulation. Endocr. Rev 2003, 24, 261–271.
- Gonçalves, P.B.; Ferreira, R.; Gasperin, B.; Oliveira, J.F. Role of angiotensin in ovarian follicular development and ovulation in mammals: A review of recent advances. Reproduction 2012, 143, 11–20.
- Speth, R.; Daubert, D.; Grove, K; Angiotensin, II. A reproductive hormone too? Regul. Pept 1999, 79, 25–40.
- Mitsube, K.; Mikuni, M.; Matousek, M.; Zackrisson, U.; Brannstrom, M. Role of the angiotensin II system in regulation of ovulation and blood flow in the rat ovary. Reproduction 2003, 125, 425–435.
- Reis, A.; Viana, G.; Pereira, V.; Santos, R. Angiotensin-(1–7) in the rabbit ovary: A novel local regulator of ovulation. Biol. Reprod 2009, 81, 566–566.
- Ferreira, R.; Gasperin, B.; Santos, J.; Rovani, M.; Santos, R.A.; Gutierrez, K.; Oliveira, J.F.; Reis, A.M.; Gonçalves, P.B. Angiotensin II profile and mRNA encoding RAS proteins during bovine follicular wave. J. Renin Angiotensin Aldosterone Syst 2011, 12, 475–482.
- Reis, A.B.; Araújo, F.C.; Pereira, V.M.; Dos Reis, A.M.; Santos, R.A.; Reis, F.M. Angiotensin (1–7) and its receptor Mas are expressed in the human testis: Implications for male infertility. J. Mol. Histol 2010, 41, 75–80.
- Reis, F.M.; Bouissou, D.R.; Pereira, V.M.; Camargos, A.F.; dos Reis, A.M.; Santos, R.A. Angiotensin-(1–7) its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary. Fertil. Steril 2011, 95, 176–181.
- Rella, M.; Elliot, J.L.; Revett, T.J.; Lanfear, J.; Phelan, A.; Jackson, R.M.; Turner, A.J.; Hooper, N.M. Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: A novel mammalian homologue of ACE. BMC Genomics 2007, doi:10.1186/1471-2164-8-194..
- Acosta, E.; Peña, Ó.; Naftolin, F.; Ávila, J.; Palumbo, A. Angiotensin II induces apoptosis in human mural granulosa-lutein cells, but not in cumulus cells. Fertil. Steril 2009, 91, 1984–1989.
- Peña, Ó.; Palumbo, A.; González-Fernández, R.; Hernández, J.; Naftolin, F.; Ávila, J. Expression of angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors in human granulosa-lutein (GL) cells: Correlation with infertility diagnoses. Fertil. Steril 2010, 93, 1601–1608.
- De Gooyer, T.; Skinner, S.; Wlodek, M.; Kelly, D.; Wilkinson-Berka, J. Angiotensin II influences ovarian follicle development in the transgenic (mRen-2) 27 and Sprague-Dawley rat. J. Endocrinol 2004, 180, 311–324.
- Pereira, V.M.; Reis, F.M.; Santos, R.A.; Cassali, G.D.; Santos, S.H.; Honorato-Sampaio, K.; dos Reis, A.M. Gonadotropin stimulation increases the expression of angiotensin-(1–7) and Mas receptor in the rat ovary. Reprod. Sci 2009, 16, 1165–1174.
- Leung, P.S.; Sernia, C. The renin–angiotensin system and male reproduction: New functions for old hormones. J. Mol. Endocrinol 2003, 30, 263–270.
- Leung, P.; Wong, T.; Chung, Y.; Chan, H. Androgen dependent expression of AT1 receptor and its regulation of anion secretion in rat epididymis. Cell Biol. Int 2002, 26, 117–122.
- Ehlers, M.R.; Riordan, J.F. Angiotensin-converting enzyme: New concepts concerning its biological role. Biochemistry 1989, 28, 5311–5318.
- Donoghue, M.; Hsieh, F.; Baronas, E.; Godbout, K.; Gosselin, M.; Stagliano, N.; Donovan, M.; Woolf, B.; Robison, K.; Jeyaseelan, R. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ. Res 2000, 87, e1–e9.
- Hubert, C.; Houot, A.-M.; Corvol, P.; Soubrier, F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J. Biol. Chem 1991, 266, 15377–15383.
- Xu, J.; Baulding, J.; Palli, S.R. Proteomics of Tribolium castaneum seminal fluid proteins: Identification of an angiotensin-converting enzyme as a key player in regulation of reproduction. J. Proteomics 2012, 78, 83–93.
- Shibahara, H.; Kamata, M.; Hu, J.; Nakagawa, H.; Obara, H.; Kondoh, N.; Shima, H.; Sato, I. Activity of testis angiotensin converting enzyme (ACE) in ejaculated human spermatozoa. Int. J. Androl 2001, 24, 295–299.
- Hagaman, J.R.; Moyer, J.S.; Bachman, E.S.; Sibony, M.; Magyar, P.L.; Welch, J.E.; Smithies, O.; Krege, J.H.; O’Brien, D.A. Angiotensin-converting enzyme and male fertility. Proc. Natl. Acad. Sci. USA 1998, 95, 2552–2557.
- Pauls, K.; Fink, L.; Franke, F. Angiotensin-converting enzyme (CD143) in neoplastic germ cells. Lab. Invest 1999, 79, 1425–1435.
- Franke, F.E.; Pauls, K.; Metzger, R.; Danilov, S.M. Angiotensin I-converting enzyme and potential substrates in human testis and testicular tumours. APMIS 2003, 111, 234–244.
- Pauls, K.; Metzger, R.; Steger, K.; Klonisch, T.; Danilov, S.; Franke, F. Isoforms of angiotensin I-converting enzyme in the development and differentiation of human testis and epididymis. Andrologia 2003, 35, 32–43.
- Tipnis, S.R.; Hooper, N.M.; Hyde, R.; Karran, E.; Christie, G.; Turner, A.J. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem 2000, 275, 33238–33243.
- Zhang, H.; Wada, J.; Hida, K.; Tsuchiyama, Y.; Hiragushi, K.; Shikata, K.; Wang, H.; Lin, S.; Kanwar, Y.S.; Makino, H. Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J. Biol. Chem 2001, 276, 17132–17139.
- Brentjens, J.; Matsuo, S.; Andres, G.; Caldwell, P.; Zamboni, L. Gametes contain angiotensin converting enzyme (kininase II). Experientia 1986, 42, 399–402.
- Ferreira, R.; Gasperin, B.; Rovani, M.; Santos, J.; Barreta, M.; Bohrer, R.; Price, C.; Gonçalves, P.B.D. Angiotensin II signaling promotes follicle growth and dominance in cattle. Endocrinology 2011, 152, 4957–4965.
- Feral, C.; le Gall, S.; Leymarie, P. Angiotensin II modulates steroidogenesis in granulosa and theca in the rabbit ovary: Its possible involvement in atresia. Eur. J. Endocrinol 1995, 133, 747–753.
- Li, Y.; Jiao, L.; Liu, R.; Chen, X.; Wang, H.; Wang, W. Localization of angiotensin II in pig ovary and its effects on oocyte maturation in vitro. Theriogenology 2004, 61, 447–459.
- Stefanello, J.R.; Barreta, M.H.; Porciuncula, P.M.; Arruda, J.N.; Oliveira, J.F.; Oliveira, M.A.; Gonçalves, P.B. Effect of angiotensin II with follicle cells and insulin-like growth factor-I or insulin on bovine oocyte maturation and embryo development. Theriogenology 2006, 66, 2068–2076.
- Yoshimura, Y.; Karube, M.; Aoki, H.; Oda, T.; Koyama, N.; Nagai, A.; Akimoto, Y.; Hirano, H.; Nakamura, Y. Angiotensin II induces ovulation and oocyte maturation in rabbit ovaries via the AT2 receptor subtype. Endocrinology 1996, 137, 1204–1211.
- Agarwal, A.; Gupta, S.; Sharma, R.K. Role of oxidative stress in female reproduction. Reprod. Biol. Endocrinol 2005, 3, 1–21.
- Gupta, S.; Goldberg, J.M.; Aziz, N.; Goldberg, E.; Krajcir, N.; Agarwal, A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil. Steril 2008, 90, 247–257.
- Ruder, E.H.; Hartman, T.J.; Goldman, M.B. Impact of oxidative stress on female fertility. Curr. Opin. Obstet Gynecol 2009, 21, 219–222.
- Ruder, E.H.; Hartman, T.J.; Blumberg, J.; Goldman, M.B. Oxidative stress and antioxidants: Exposure and impact on female fertility. Hum. Reprod. Update 2008, 14, 345–357.
- Benicky, J.; Sánchez-Lemus, E.; Pavel, J.; Saavedra, J.M. Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell. Mol. Neurobiol 2009, 29, 781–792.
- Inserra, F.; Martínez-Maldonado, M. Inflammation and the metabolic syndrome: Role of angiotensin II and oxidative stress. Curr. Hypertens. Rep 2006, 8, 191–198.
- Yoshimura, Y.; Koyama, N.; Karube, M.; Oda, T.; Akiba, M.; Yoshinaga, A.; Shiokawa, S.; Jinno, M.; Nakamura, Y. Gonadotropin stimulates ovarian renin–angiotensin system in the rabbit. J. Clin. Invest 1994, 93, 180–187.
- Daud, A.I.; Bumpus, F.M.; Husain, A. Characterization of angiotensin I-converting enzyme (ACE)-containing follicles in the rat ovary during the estrous cycle and effects of ACE inhibitor on ovulation. Endocrinology 1990, 126, 2927–2935.
- Costa, A.P.; Fagundes-Moura, C.R.; Pereira, V.M.; Silva, L.F.; Vieira, M.A.R.; Santos, R.A.; Dos Reis, A.M. Angiotensin-(1–7): A novel peptide in the ovary. Endocrinology 2003, 144, 1942–1948.
- Honorato-Sampaio, K.; Pereira, V.M.; Santos, R.A.; Reis, A.M. Evidence that angiotensin-(1–7) is an intermediate of gonadotrophin-induced oocyte maturation in the rat preovulatory follicle. Exp. Physiol 2012, 97, 642–650.
- Cushman, D.; Cheung, H. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem. Pharmacol 1971, 20, 1637–1648.
- Langford, K.G.; Zhou, Y.; Russell, L.D.; Wilcox, J.N.; Bernstein, K.E. Regulated expression of testis angiotensin-converting enzyme during spermatogenesis in mice. Biol. Reprod 1993, 48, 1210–1218.
- Köhn, F.-M.; Dammshäuser, I.; Neukamm, C.; Renneberg, H.; Siems, W.-E.; Schill, W.-B.; Aumüller, G. Ultrastructural localization of angiotensin-converting enzyme in ejaculated human spermatozoa. Hum. Reprod 1998, 13, 604–610.
- Nikolaeva, M.A.; Balyasnikova, I.V.; Alexinskaya, M.A.; Metzger, R.; Franke, F.E.; Albrecht, R.F.; Kulakov, V.I.; Sukhikh, G.T.; Danilov, S.M. Testicular isoform of angiotensin I-converting enzyme (ACE, CD143) on the surface of human spermatozoa: Revelation and quantification using monoclonal antibodies. Am. J. Reprod. Immunol 2006, 55, 54–68.
- Yokoyama, M.; Takada, Y.; Iwata, H.; Ochi, K.; Takeuchi, M.; Hiwada, K.; Kokubu, T. Correlation between angiotensin-converting enzyme activity and histologic patterns in benign prostatic hypertrophy tissue. J. Urol 1982, 127, 368–379.
- Dacheux, J.-L.; Belleannée, C.; Guyonnet, B.; Labas, V.; Teixeira-Gomes, A.-P.; Ecroyd, H.; Druart, X.; Gatti, J.-L.; Dacheux, F. The contribution of proteomics to understanding epididymal maturation of mammalian spermatozoa. Syst. Biol. Reprod. Med 2012, 58, 197–210.
- Cesari, A.; de Monclus, M. L.; Tejón, G.P.; Clementi, M.; Fornes, M.W. Regulated serine proteinase lytic system on mammalian sperm surface: There must be a role. Theriogenology 2010, 74, 699–711.
- Yamaguchi, R.; Yamagata, K.; Ikawa, M.; Moss, S.B.; Okabe, M. Aberrant distribution of ADAM3 in sperm from both angiotensin-converting enzyme (Ace)-and calmegin (Clgn)-deficient mice. Biol. Reprod 2006, 75, 760–766.
- Zhu, G.Z.; Gupta, S.; Myles, D.G.; Primakoff, P. Testase 1 (ADAM 24) a sperm surface metalloprotease is required for normal fertility in mice. Mol. Reprod. Dev 2009, 76, 1106–1114.
- Köhn, F.M.; Miska, W.; Schill, W.B. Release of angiotensin-converting enzyme (ACE) from human spermatozoa during capacitation and acrosome reaction. J. Androl 1995, 16, 259–265.
- Kamata, M.; Hu, J.; Shibahara, H.; Nakagawa, H. Assay of testicular angiotensin-converting enzyme activity in human spermatozoa. Int. J. Androl 2001, 24, 225–231.
- Kondoh, G.; Tojo, H.; Nakatani, Y.; Komazawa, N.; Murata, C.; Yamagata, K.; Maeda, Y.; Kinoshita, T.; Okabe, M.; Taguchi, R. Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization. Nat. Med 2005, 11, 160–166.
- Deguchi, E.; Tani, T.; Watanabe, H.; Yamada, S.; Kondoh, G. Dipeptidase-inactivated tACE action in vivo: Selective inhibition of sperm-zona pellucida binding in the mouse. Biol. Reprod 2007, 77, 794–802.
- Fuchs, S.; Frenzel, K.; Hubert, C.; Lyng, R.; Muller, L.; Michaud, A.; Xiao, H.D.; Adams, J.W.; Capecchi, M.R.; Corvol, P. Male fertility is dependent on dipeptidase activity of testis ACE. Nat. Med 2005, 11, 1140–1142.
- Leisle, L.; Parkin, E.T.; Turner, A.J.; Hooper, N.M. Angiotensin-converting enzyme as a GPIase: A critical reevaluation. Nat. Med 2005, 11, 1139–1140.
- Leal, M.C.; Pinheiro, S.V.; Ferreira, A.J.; Santos, R.A.; Bordoni, L.S.; Alenina, N.; Bader, M.; França, L.R. The role of angiotensin-(1–7) receptor Mas in spermatogenesis in mice and rats. J. Anat 2009, 214, 736–743.
- Kondoh, G.; Watanabe, H.; Tashima, Y.; Maeda, Y.; Kinoshita, T. Testicular angiotensin-converting enzyme with different glycan modification: Characterization on glycosylphosphatidylinositol-anchored protein releasing and dipeptidase activities. J. Biochem. 2009, 145, 115–121.
- Inoue, N.; Ikawa, M.; Isotani, A.; Okabe, M. The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature 2005, 434, 234–238.
- Hudecova, M.; Holte, J.; Olovsson, M.; Larsson, A.; Berne, C.; Sundstrom-Poromaa, I. Prevalence of the metabolic syndrome in women with a previous diagnosis of polycystic ovary syndrome: Long-term follow-up. Fertil. Steril 2011, 96, 1271–1274.
- Jia, H.; Wang, B.; Yu, L.; Jiang, Z. Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with polycystic ovary syndrome: A meta-analysis. J. Renin Angiotensin Aldosterone Syst 2012, 14, 255–262.
- Gard, P.R. Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: A snapshot review. Int. J. Mol. Epidemiol. Genet 2010, 1, 145–157.
- Celik, O.; Yesilada, E.; Hascalik, S.; Celik, N.; Sahin, I.; Keskin, L.; Ozerol, E. Angiotensin-converting enzyme gene polymorphism and risk of insulin resistance in PCOS. Reprod. Biomed. Online 2010, 20, 492–498.
- Che, Y.; Cao, Y.; Wu, X.; Sun, H.-X.; Liang, F.; Yi, L.; Wang, Y. Association between ACE gene I/D polymorphisms and hyperandrogenism in women with polycystic ovary syndrome (PCOS) and controls. BMC Med. Genet 2009, doi:10.1186/1471-2350-10-64..
- Nandi, A.; Wang, X.; Accili, D.; Wolgemuth, D.J. The effect of insulin signaling on female reproductive function independent of adiposity and hyperglycemia. Endocrinology 2010, 151, 1863–1871.
- Vandermolen, D.T.; Ratts, V.S.; Evans, W.S.; Stovall, D.W.; Kauma, S.W.; Nestler, J.E. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil. Steril 2001, 75, 310–315.
- Du Plessis, S.S.; Cabler, S.; McAlister, D.A.; Sabanegh, E.; Agarwal, A. The effect of obesity on sperm disorders and male infertility. Nat. Rev. Urol 2010, 7, 153–161.
- Sermondade, N.; Faure, C.; Fezeu, L.; Lévy, R.; Czernichow, S. Obesity and increased risk for oligozoospermia and azoospermia. Arch. Intern. Med 2012, 172, 440–442.
- Riera-Fortuny, C.; Real, J.T.; Chaves, F.J.; Morales-Suarez-Varela, M.; Martinez-Triguero, M.L.; Morillas-Arino, C.; Hernández-Mijares, A. The relation between obesity, abdominal fat deposit and the angiotensin-converting enzyme gene I/D polymorphism and its association with coronary heart disease. Int. J. Obes 2005, 29, 78–84.
- Muciaccia, B.; Pensini, S.; Culasso, F.; Padula, F.; Paoli, D.; Gandini, L.; Di Veroli, C.; Bianchini, G.; Stefanini, M.; D’Agostino, A. Higher clusterin immunolabeling and sperm DNA damage levels in hypertensive men compared with controls. Hum. Reprod 2012, 27, 2267–2276.
- Ramalho-Santos, J.; Amaral, S.; Oliveira, P.J. Diabetes and the impairment of reproductive function: Possible role of mitochondria and reactive oxygen species. Curr. Diabetes Rev 2008, 4, 46–54.
- Gwathmey, T.M.; Pendergrass, K.D.; Reid, S.D.; Rose, J.C.; Diz, D.I.; Chappell, M.C. Angiotensin-(1–7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin II within the cell nucleus. Hypertension 2010, 55, 166–171.
- Dikalov, S.I.; Nazarewicz, R.R. Angiotensin II-induced production of mitochondrial reactive oxygen species: Potential mechanisms and relevance for cardiovascular disease. Antioxid. Redox Signal 2012, 19, 1085–1094.
- Hacıhanefioglu, B.; Seyisoglu, H.; Karsıdag, K.; Elter, K.; Aksu, F.; Yılmaz, T.; Gurol, A.O. Influence of insulin resistance on total renin level in normotensive women with polycystic ovary syndrome. Fertil. Steril 2000, 73, 261–265.
- Franks, S. Genetic and environmental origins of obesity relevant to reproduction. Reprod. Biomed. Online 2006, 12, 526–531.
- Nawano, M.; Anai, M.; Funaki, M.; Kobayashi, H.; Kanda, A.; Fukushima, Y.; Inukai, K.; Ogihara, T.; Sakoda, H.; Onishi, Y. Imidapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat. Metabolism 1999, 48, 1248–1255.
- Muscogiuri, G.; Chavez, A.O.; Gastaldelli, A.; Perego, L.; Tripathy, D.; Saad, M.J.; Velloso, L.; Folli, F. The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. Curr. Vasc. Pharmacol 2008, 6, 301–312.
- Okeahialam, B.; Amadi, K.; Ameh, A. Effect of lisnopril, an angiotensin converting enzyme (ACE) inhibitor on spermatogenesis in rats. Syst. Biol. Reprod. Med 2006, 52, 209–213.
- Siems, W.E.; Maul, B.; Wiesner, B.; Becker, M.; Walther, T.; Rothe, L.; Winkler, A. Effects of kinins on mammalian spermatozoa and the impact of peptidolytic enzymes. Andrologia 2003, 35, 44–54.
- Monsees, T.K.; Miska, W.; Schill, W.-B. Characterization of kininases in testicular cells. Immunopharmacology 1996, 32, 169–171.
- Saha, L.; Garg, S.K.; Bhargava, V.K.; Mazumdar, S. Role of angiotensin-converting enzyme inhibitor, lisinopril, on spermatozoal functions in rats. Method Find. Exp. Clin. Pharmacol 2000, 22, 159–162.
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