Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

Musicki, Biljana; Hannan, Johanna L.; Lagoda, Gwen A.; Bivalacqua, Trinity J.; Burnett, Arthur L.

doi:10.1111/andr.12218

Cited by 27 publications

(23 citation statements)

References 37 publications

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“…eNOS and nNOS uncoupling, measured indirectly as a decreased ratio of active dimers to inactive monomers, refers to a switch in the enzyme's activity from NO-producing to a predominantly superoxide-producing enzyme (Fostermann & Sessa 2012). Previous studies demonstrated eNOS uncoupling in the penis of T2DM rats (Musicki et al, 2016) and nNOS uncoupling in the rat penile arteries under conditions of insulin resistance (Sanchez et al, 2012). We now extend these findings to the erectile tissue of T2DM men with ED, showing that both eNOS and nNOS are uncoupled.…”

Section: Discussionmentioning

confidence: 98%

“…The prototype NADPH oxidase NOX2/gp91phox possesses cytosolic subunits (p47phox, p67phox, or homologues) and membrane-bound subunits (gp91phox and p22phox), which form a functional enzyme complex upon activation (Brandes et al, 2014). Increased protein expression of NOX2 subunits has been demonstrated in the penis of T2DM rats (Long et al, 2012; Musicki et al, 2016) and mice (Nunes et al, 2015). We now report upregulated NADPH oxidase catalytic subunit gp91phox in the human T2DM penis, implying activated NADPH oxidase as a source of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Basic scientific studies indicate that increased oxidative stress and reduced nitric oxide (NO) bioavailability are the major derangements underlying the development and progression of vasculogenic and neurogenic ED associated with DM (Long et al, 2012; Vernet et al, 1995; Luttrell et al, 2008; Carneiro et al, 2010; Elliati et al, 2013; Albersen et al, 2011; Chiou et al, 2010; Oger et al, 2014; Kataoka et al 2014; Musicki et al, 2016; Xie et al, 2007; Kovanecz et al, 2009; Chitaley 2009; Nunes et al, 2015; Wingard et al, 2007; Sanchez et al, 2012). In diabetic patients ED is similarly related to reduced NOS activity, as evidenced by elevated arginase activity (Bivalacqua et al, 2001) and decreased nNOS protein expression (Dashwood et al, 2011), nitrate/nitrite (Tuncayengin et al, 2003) and cGMP content (Angulo et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction

Musicki¹,

Burnett²

2017

Andrology

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Erectile dysfunction (ED) associated with type 2 diabetes mellitus (T2DM) involves dysfunctional nitric oxide (NO) signaling and increased oxidative stress in the penis. However, the mechanisms of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) dysregulation, and the sources of oxidative stress, are not well defined, particularly at the human level. The objective of this study was to define whether uncoupled eNOS and nNOS, and NADPH oxidase upregulation, contribute to the pathogenesis of ED in T2DM men. Penile erectile tissue was obtained from 9 T2DM patients with ED who underwent penile prosthesis surgery for ED, and from 6 control patients without T2DM or ED who underwent penectomy for penile cancer. The dimer-to-monomer protein expression ratio, an indicator of uncoupling for both eNOS and nNOS, total protein expressions of eNOS and nNOS, as well as protein expressions of NADPH oxidase catalytic subunit gp91phox (an enzymatic source of oxidative stress) and 4-hydroxy-2-nonenal [4-HNE] and nitrotyrosine (markers of oxidative stress) were measured by Western blot in this tissue. In the erectile tissue of T2DM men, eNOS and nNOS uncoupling and protein expressions of NADPH oxidase subunit gp91phox, 4-HNE- and nitrotyrosine-modified proteins were significantly (p<0.05) increased compared to control values. Total eNOS and nNOS protein expressions were not significantly different between the groups. In conclusion, mechanisms of T2DM-associated ED in the human penis may involve uncoupled eNOS and nNOS and NADPH oxidase upregulation. Our description of molecular factors contributing to the pathogenesis of T2DM-associated ED at the human level is relevant for advancing clinically therapeutic approaches to restore erectile function in T2DM patients.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction

Musicki¹,

Burnett²

2017

Andrology

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“…Recent studies have shown that increased oxidative stress and NOS uncoupling are accepted as a mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type DM (Musicki & Burnett, 2017;Musicki, Hannan, Lagoda, Bivalacqua, & Burnett, 2016). But NOS uncoupling and penile ROS levels have not been evaluated in this study.…”

mentioning

confidence: 92%

Re: Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats. Alkan E, Ugan RA, Basar MM, Halici Z, Karakus E, Balbay MD, Un H.Andrologia. 2016 May 4. doi: 10.1111/and.12607

Özbek

2018

Andrologia

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Read with great interest the article recently published entitled "Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats." by Alkan et al. in Andrologia (Alkan et al., 2017). The authors have examined the role of endothelin receptors and the relationship with nitric oxide synthase in impaired erectile response in diabetic rats. While endothelin-1 (ET-1), TNFα and iNOS gene expressions increased, erectile function decreased in the DM group compared to the healthy group at the end of the treatment with bosentan (BOS), an ET-1 receptor antagonist. eNOS, ET-RA and ET-RB gene expressions decreased in the DM group in a dose-dependent manner. The manuscript planned to evaluate the molecular mechanism of the protective effect of ET receptor antagonist on DM-induced ED. However, several methodological flaws hamper the overall quality of the experiment. Although the apomorphine test has been used to test erectile function, it would be better if in vitro organ bath was used for penile strips together with cavernosal nerve stimulation and intracavernosal pressure study to evaluate nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling pathway and cavernosal pressure measurement respectively (Liu et al., 2016; Martínez-Salamanca et al., 2016). Researchers should have assessed physiological muscle tone as an index to erectile function, that is intracavernosal pressure, assessment of nitric oxide production and cGMP levels which are better indicators of eNOS enzyme functions. The authors tested the preventative effect of BOS just after the onset of hyperglycaemia, but the therapeutic effect of ET-1 antagonist was not reported. It would be better if therapeutic group, 4 weeks after the injection of STZ, was used. The therapeutic group is important because erectile dysfunction is a complication of diabetes, and it requires time to develop. To test the therapeutic effect of an agent in DM, complications of DM must be established (Konturek et al., 2010; Usta et al., 2006). Recent studies have shown that increased oxidative stress and NOS uncoupling are accepted as a mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type DM (Musicki & Burnett, 2017; Musicki, Hannan, Lagoda, Bivalacqua, & Burnett, 2016). But NOS uncoupling and penile ROS levels have not been evaluated in this study. Although neuropathic complications are common in DM, the NOS activity has not been investigated. It would be better if protein expressions were studied as these are better markers than gene expressions. Endothelial dysfunction in diabetes is characterised by a reduced nitric oxide bioavailability (Shi & Vanhoutte, 2017). There is no information in the literature about the protective role of ET-1 antagonist on oxidative stress, prevention of NOS uncoupling and NO bioavailability. It would be better to study these molecular tests. Furthermore, bosentan is a nonspecific ET-1 receptor antagonist. Bosentan cannot be used to assess effects on erectil...

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“…Alterations of the NO-cGMP signaling pathway have been implicated as a major pathomechanism for ED [ 1 ]. ED in diabetic, hypertensive, and hypercholesterolemic animals has been associated with downregulation of eNOS and nNOS expression in the penis, as well as impaired cavernosal relaxation [ 19 – 21 ]. Elevated oxidative stress has also been associated with ED, since superoxide anion can react with NO, reducing NO bioavailability [ 19 , 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

A novel experimental model of erectile dysfunction in rats with heart failure using volume overload

Silva

Veiga

et al. 2017

PLoS ONE

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BackgroundPatients with heart failure (HF) display erectile dysfunction (ED). However, the pathophysiology of ED during HF remains poorly investigated.ObjectiveThis study aimed to characterize the aortocaval fistula (ACF) rat model associated with HF as a novel experimental model of ED. We have undertaken molecular and functional studies to evaluate the alterations of the nitric oxide (NO) pathway, autonomic nervous system and oxidative stress in the penis.MethodsMale rats were submitted to ACF for HF induction. Intracavernosal pressure in anesthetized rats was evaluated. Concentration-response curves to contractile (phenylephrine) and relaxant agents (sodium nitroprusside; SNP), as well as to electrical field stimulation (EFS), were obtained in the cavernosal smooth muscle (CSM) strips from sham and HF rats. Protein expression of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) and phosphodiestarese-5 in CSM were evaluated, as well as NOX2 (gp91phox) and superoxide dismutase (SOD) mRNA expression. SOD activity and thiobarbituric acid reactive substances (TBARs) were also performed in plasma.ResultsHF rats display erectile dysfunction represented by decreased ICP responses compared to sham rats. The neurogenic contractile responses elicited by EFS were greater in CSM from the HF group. Likewise, phenylephrine-induced contractions were greater in CSM from HF rats. Nitrergic response induced by EFS were decreased in the cavernosal tissue, along with lower eNOS, nNOS and phosphodiestarese-5 protein expressions. An increase of NOX2 and SOD mRNA expression in CSM and plasma TBARs of HF group were detected. Plasma SOD activity was decreased in HF rats.ConclusionED in HF rats is associated with decreased NO bioavailability in erectile tissue due to eNOS/nNOS dowregulation and NOX2 upregulation, as well as hypercontractility of the penis. This rat model of ACF could be a useful tool to evaluate the molecular alterations of ED associated with HF.

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Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

Cited by 27 publications

References 37 publications

Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction

Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction

Re: Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats. Alkan E, Ugan RA, Basar MM, Halici Z, Karakus E, Balbay MD, Un H.Andrologia. 2016 May 4. doi: 10.1111/and.12607

A novel experimental model of erectile dysfunction in rats with heart failure using volume overload

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