Role of the soluble guanylyl cyclase α1-subunit in mice corpus cavernosum smooth muscle relaxation

Nimmegeers, Sofie; Sips, Patrick; Buys, Emmanuel; Decaluwé, Kelly; Brouckaert, Peter; Voorde, Johan Van de

doi:10.1038/sj.ijir.3901627

Cited by 17 publications

(10 citation statements)

References 37 publications

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“…However, only the α 1 β 1 and α 2 β 1 heterodimers are catalytically active [31]. Studies suggested that sGCα 1 β 1 is predominantly expressed in CC and is the most important sGC heterodimer responsible for corporal smooth muscle relaxation [32–34]. In aorta from sGCα 1 −/− mice, the resveratrol‐ and quercetin‐induced relaxations were significantly inhibited, confirming the NO/sGC dependency by which polyphenols relax arteries.…”

Section: Discussionmentioning

confidence: 95%

Relaxant and Antioxidant Capacity of the Red Wine Polyphenols, Resveratrol and Quercetin, on Isolated Mice Corpora Cavernosa

Boydens

Pauwels

Decaluwé

et al. 2015

The Journal of Sexual Medicine

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Introduction The red wine polyphenols resveratrol and quercetin are known for their vasorelaxant and antioxidant capacity, which is assumed to rely on the activation of the nitric oxide (NO)/soluble guanylyl cyclase (sGC) pathway. Vasodilators as well as antioxidants can regulate penile erection and be beneficial for the treatment of erectile dysfunction (ED). Aims The goal of this study was to evaluate the NO/sGC dependency of the relaxant effect of resveratrol and quercetin on mice aorta and corpora cavernosa (CC), as well as to explore their influence on oxidative stress-induced ED. Methods Isolated mice aorta and CC were mounted for isometric tension recordings into organ baths. Cumulative concentration-response curves were constructed for resveratrol and quercetin in the absence/presence of inhibitors of the NO/sGC pathway. In addition, in CC the effect of resveratrol and quercetin was studied on NO-mediated relaxations using acetylcholine (Ach), sodium nitroprusside (SNP), and electrical field stimulation (EFS). In certain experiments, corporal tissues were exposed to oxidative stress using palmitic acid (PA, 0.5 mM). Main Outcome Measures Corporal responses to resveratrol and quercetin were measured in the presence/absence of inhibitors of different molecular pathways. The effect of resveratrol and quercetin incubation on Ach-, SNP-, or EFS-mediated responses was explored in the presence/absence of PA. Results While both polyphenols are potent vasodilators of mice aorta, only resveratrol relaxes mice CC. The relaxation response to resveratrol on aorta was diminished in sGCα1−/− mice, but not on CC. The polyphenols did not influence Ach-, SNP-, or EFS-mediated relaxations as such. Resveratrol, but not quercetin, was able to significantly reverse PA-induced decrease of EFS relaxations. Conclusion The red wine compound resveratrol, but not quercetin, relaxes isolated mice CC concentration-dependently through mechanisms independent of the NO/sGC pathway. Resveratrol is a more potent antioxidant than quercetin, being able to restore decreased neuronal NO responses in mice CC.

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Section: Discussionmentioning

confidence: 95%

Relaxant and Antioxidant Capacity of the Red Wine Polyphenols, Resveratrol and Quercetin, on Isolated Mice Corpora Cavernosa

Boydens

Pauwels

Decaluwé

et al. 2015

The Journal of Sexual Medicine

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“…The enzyme, which catalyzes the conversion of GTP into cGMP, consists of two different subunits and contains a prosthetic heme group that mediates up to 400-fold activation by NO. Nimmegeers et al (2008) assessed the functional importance of the sGC␣ 1 ␤ 1 isoform in CC from male sGC␣ 1 (Ϫ/Ϫ) and wild-type mice. The relaxation to endogenous NO (from acetylcholine, bradykinin, and electrical field stimulation) was nearly abolished in the sGC␣ 1 (Ϫ/Ϫ) CC.…”

Section: J Nitric Oxide and Cgmp Signalingmentioning

confidence: 99%

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

2011

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“…High concentrations of cGMP produced by activated sGC modulate functions of numerous enzymes, such as cyclic nucleotide phosphodiesterases, cGMP-gated ion channels, and cGMP-dependent protein kinases (PGKs). Recently, the vital importance of sGC for mammalian physiology was directly confirmed by generation of sGC knock-out mice (7)(8)(9). The absence of sGC protein resulted in a significant increase in blood pressure, complete loss of NO-dependent aortic relaxation, and inhibition of platelet aggregation in knock-out animals, which died prematurely at the age of 4 weeks because of severe gastrointestinal disorders (7).…”

mentioning

confidence: 99%

“…Vascular smooth muscle and endothelial cells express predominantly ␣ 1 -and ␤ 1 -subunits (12). The functional importance of ␣ 1 /␤ 1 sGC was demonstrated by the significantly decreased relaxing effects of major vasodilators (acetylcholine, NO, YC-1, and BAY41-2272) in the ␣ 1 sGC knock-out mice of both genders (9). sGC function is affected not only by NO, but also by regulation of the expression of sGC subunits at transcriptional and post-transcriptional levels.…”

mentioning

confidence: 99%

α1 Soluble Guanylyl Cyclase (sGC) Splice Forms as Potential Regulators of Human sGC Activity

Sharina

Jeleń

Bogatenkova

et al. 2008

Journal of Biological Chemistry

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Soluble guanylyl cyclase (sGC), a key protein in the NO/cGMP signaling pathway, is an obligatory heterodimeric protein composed of one ␣-and one ␤-subunit. The ␣ 1 /␤ 1 sGC heterodimer is the predominant form expressed in various tissues and is regarded as the major isoform mediating NO-dependent effects such as vasodilation. We have identified three new ␣ 1 sGC protein variants generated by alternative splicing. The 363 residue N1-␣ 1 sGC splice variant contains the regulatory domain, but lacks the catalytic domain. The shorter N2-␣ 1 sGC maintains 126 N-terminal residues and gains an additional 17 unique residues. The C-␣ 1 sGC variant lacks 240 N-terminal amino acids, but maintains a part of the regulatory domain and the entire catalytic domain. Q-PCR of N1-␣ 1 , N2-␣ 1 sGC mRNA levels together with RT-PCR analysis for C-␣ 1 sGC demonstrated that the expression of the ␣ 1 sGC splice forms vary in different human tissues indicative of tissue-specific regulation. Functional analysis of the N1-␣ 1 sGC demonstrated that this protein has a dominant-negative effect on the activity of sGC when coexpressed with the ␣ 1 /␤ 1 heterodimer. The C-␣ 1 sGC variant heterodimerizes with the ␤ 1 subunit and produces a fully functional NO-and BAY41-2272-sensitive enzyme. We also found that despite identical susceptibility to inhibition by ODQ, intracellular levels of the 54-kDa C-␣ 1 band did not change in response to ODQ treatments, while the level of 83 kDa ␣ 1 band was significantly affected by ODQ. These studies suggest that modulation of the level and diversity of splice forms may represent novel mechanisms modulating the function of sGC in different human tissues.Since the studies of the late 1970s and early 1980s, which underlined the obligatory role of the endothelium in mediating acetylcholine-induced vasodilatation, nitric oxide (NO) has been recognized as an endogenous nitrovasodilator that mediates the local regulation of basal arterial tone (1-4). Many of the physiological functions of NO in the cardiovascular, neuronal, gastrointestinal, and other systems are mediated through its primary receptor, soluble guanylyl cyclase (sGC).3 The hemecontaining sGC heterodimer converts guanosine triphosphate into the secondary messenger guanosine 3Ј:5Ј-cyclic monophosphate (cGMP). The sGC activity increases more than 200-fold in response to NO (5,6). High concentrations of cGMP produced by activated sGC modulate functions of numerous enzymes, such as cyclic nucleotide phosphodiesterases, cGMP-gated ion channels, and cGMP-dependent protein kinases (PGKs). Recently, the vital importance of sGC for mammalian physiology was directly confirmed by generation of sGC knock-out mice (7-9). The absence of sGC protein resulted in a significant increase in blood pressure, complete loss of NO-dependent aortic relaxation, and inhibition of platelet aggregation in knock-out animals, which died prematurely at the age of 4 weeks because of severe gastrointestinal disorders (7).Four sGC isoforms, products of four genes, have been identified so...

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Role of the soluble guanylyl cyclase α1-subunit in mice corpus cavernosum smooth muscle relaxation

Cited by 17 publications

References 37 publications

Relaxant and Antioxidant Capacity of the Red Wine Polyphenols, Resveratrol and Quercetin, on Isolated Mice Corpora Cavernosa

Relaxant and Antioxidant Capacity of the Red Wine Polyphenols, Resveratrol and Quercetin, on Isolated Mice Corpora Cavernosa

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

α1 Soluble Guanylyl Cyclase (sGC) Splice Forms as Potential Regulators of Human sGC Activity

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