cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function

Jaumann, Mirko; Dettling, Juliane; Gubelt, Martin; Zimmermann, Ulrike; Gerling, Andrea; Paquet-Durand, François; Feil, Susanne; Wolpert, Samuel M.; Franz, Christoph; Varakina, Ksenya; Xiong, Hao; Brandt, N. J.; Kuhn, Stephanie; Geisler, H; Rohbock, Karin; Ruth, Peter; Schlossmann, Jens; Hütter, Joachim; Sandner, Peter; Feil, Robert; Engel, Jutta; Knipper, Marlies; Rüttiger, Lukas

doi:10.1038/nm.2634

Cited by 80 publications

(98 citation statements)

References 59 publications

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“…This Cys-42 is ideally located to modulate the interaction with the RhoA GTPase depending on the redox state of the kinase, with disulfide formation limiting the phosphoactivation and anti-apoptotic signaling the GTPase would otherwise afford in the absence of Cys-42 oxidation. Pharmacological inhibition of PDE5 also protected hair cells from noise-induced cell death and hearing loss (38), perhaps consistent with disulfide activation of PKG I␣ being a generic mechanism of cell death in different cell types.…”

Section: Discussionsupporting

confidence: 54%

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Prysyazhna¹,

Burgoyne²,

Scotcher³

et al. 2016

Journal of Biological Chemistry

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Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG I␣ attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG I␣ disulfide formation. To investigate the role of PKG I␣ disulfide dimerization in the development of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG I␣ knock-in (KI) mice. Echocardiography showed that doxorubicin treatment caused loss of myocardial tissue and depressed left ventricular function in WT mice. Doxorubicin also reduced pro-survival signaling and increased apoptosis in WT hearts. In contrast, KI mice were markedly resistant to the dysfunction induced by doxorubicin in WTs. In follow-on experiments the influence of the PDE5 inhibitor tadalafil on the development of doxorubicin-induced cardiomyopathy in WT and KI mice was investigated. In WT mice, co-administration of tadalafil with doxorubicin reduced PKG I␣ oxidation caused by doxorubicin and also protected against cardiac injury and loss of function. KI mice were again innately resistant to doxorubicin-induced cardiotoxicity, and therefore tadalafil afforded no additional protection. Doxorubicin decreased phosphorylation of RhoA (Ser-188), stimulating its GTPase activity to activate Rho-associated protein kinase (ROCK) in WTs. These pro-apoptotic events were absent in KI mice and were attenuated in WTs coadministered tadalafil. PKG I␣ disulfide formation triggers cardiac injury, and this initiation of maladaptive signaling can be blocked by pharmacological therapies that elevate cGMP, which binds kinase to limit its oxidation.

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Section: Discussionsupporting

confidence: 54%

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Prysyazhna¹,

Burgoyne²,

Scotcher³

et al. 2016

Journal of Biological Chemistry

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“…We also showed that the PDE5 inhibitor vardenafil, which is used for the treatment of erectile dysfunction, dramatically potentiated the anticancer effects of EGCG without affecting normal cells. The clinical value of our findings is appreciable, because PDE5 inhibitors are widely used drugs approved by the FDA for chronic use (36). Hepatotoxicity is the well-known adverse effect of high-dose EGCG (37), and, in some cases, elevation of transaminases ALT/AST has been observed in clinical trials (13).…”

Section: Pde5 Is Overexpressed In Various Types Of Human Cancer and mentioning

confidence: 67%

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis

Kumazoe

Sugihara²,

Tsukamoto³

et al. 2013

J. Clin. Invest.

111

215

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The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

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“…In conclusion, an increasing number of studies have now demonstrated that the counting of IHC ribbons after hearing loss, for example, in aged specimens [62,64] , or after an acoustic trauma [22,31,32,61,75,76] , or after intake of aminoglycoside [77,78] , can be a first indication of the loss of IHC synapses and AN integrity, independent of (elevated) hearing thresholds.…”

Section: Molecular Biomarker For Dissection Of the Ihc Phenotype And mentioning

confidence: 91%

Biomarkers for Hearing Dysfunction: Facts and Outlook

Rüttiger

Zimmermann

Knipper³

2017

ORL

Self Cite

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In medicine, biomarkers are a metric for disease state. More generally, a biomarker is anything that can be used as an indicator for a particular disease state or any physiological state of an organism. Here, we introduce functional and molecular biomarkers that are useful for categorizing defined subtypes of hearing disorder, which can help to selectively trace a particular dysfunction of the inner ear and the auditory pathway to disease.

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cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function

Cited by 80 publications

References 59 publications

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis

Biomarkers for Hearing Dysfunction: Facts and Outlook

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