News Item
Biochemistry & Molecular Biology
Emil Martin
Summary: The susceptibility of nitric oxide to scavenging and oxidation restricts its availability and signaling role. However, recent studies suggest that a NO-ferroheme adduct is resistant to these limitations and may function as an alternative signaling molecule derived from nitric oxide in vasculature.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Cheng Zhong, Minze Xu, Senguel Boral, Holger Summer, Falk-Bach Lichtenberger, Cem Erdogan, Maik Gollasch, Stefan Golz, Pontus B. Persson, Johanna Schleifenbaum, Andreas Patzak, Pratik H. Khedkar
Summary: Aging affects the downstream signaling of the endothelial nitric oxide system in vascular smooth muscle, leading to compromised vasorelaxation even in the absence of histopathological alterations. The reduced expression of sGC and PDE5 may contribute to the impaired vasorelaxation in aged vessels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Shingo Kimura, Naoki Kawamorita, Yoku Kikuchi, Tomohiko Shindo, Yuichi Ishizuka, Yoichi Satake, Takuma Sato, Hideaki Izumi, Shinichi Yamashita, Satoshi Yasuda, Hiroaki Shimokawa, Akihiro Ito
Summary: This study aimed to evaluate the effect of Low-energy shock wave therapy (LESW) on ischemic-induced overactive bladder in rats and investigate its therapeutic mechanisms. The results showed that LESW treatment significantly improved bladder function recovery, possibly through the activation of the sGC-cGMP pathway.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Yue Dai, Emily M. Faul, Arnab Ghosh, Dennis J. Stuehr
Summary: Nitric oxide (NO) signaling in biology relies on its activating cyclic guanosine monophosphate (cGMP) production by the NO receptor soluble guanylyl cyclase (sGC). Physiological levels of NO trigger the mobilization of heme to immature sGC, leading to the construction of functional sGC heterodimers and increased active sGC levels. The process involves glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-heme complexes and the chaperone hsp90.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Physiology
Malte Verheyen, Michelle Puschkarow, Stefanie Gnipp, Doris Koesling, Marcus Peters, Evanthia Mergia
Summary: In this study, we investigated the role of NO-GC isoforms in respiration by measuring lung function parameters of isoform-specific knockout mice. Our findings suggest that NO-GC1-derived cGMP plays a significant role in regulating airway tone, while NO-GC2 affects tissue elasticity and airway reactivity.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2022)
Article
Cell Biology
Ayako Tonoki, Saki Nagai, Zhihua Yu, Tong Yue, Sizhe Lyu, Xue Hou, Kotomi Onuki, Kaho Yabana, Hiroki Takahashi, Motoyuki Itoh
Summary: This study identified the gyc beta gene as a negative regulator of age-related memory impairment (AMI) in fruit flies. It was shown that inhibition of the NO-sGC pathway enhanced intermediate-term memory (ITM) in aged individuals, suggesting a potential mechanism underlying memory impairment in aging.
Article
Cardiac & Cardiovascular Systems
Joseph C. Galley, Megan P. Miller, Subramaniam Sanker, Mingjun Liu, Iraida Sharina, Emil Martin, Delphine Gomez, Adam C. Straub
Summary: This study identifies Forkhead box subclass O protein 4 (FoxO4) as a key transcriptional regulator of GUCY1B3 expression, coding for sGC13 protein in human and animal smooth muscle cells (SMCs). This discovery may have important implications for future antihypertensive and vasodilatory therapies targeting NO production, sGC, or FoxO transcription factors.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2022)
Review
Cardiac & Cardiovascular Systems
Alexandra Petraina, Cristian Nogales, Thomas Krahn, Hermann Mucke, Thomas F. Luscher, Rodolphe Fischmeister, David A. Kass, John C. Burnett, Adrian J. Hobbs, Harald H. H. W. Schmidt
Summary: Mechanism-based therapy focused on understanding disease pathways at the molecular level is still rare in cardiovascular medicine, but recent drug developments centered around cGMP offer promising personalized treatment options. By modulating cGMP synthesis or breakdown, these drugs show potential for protective effects across various cardiac conditions.
CARDIOVASCULAR RESEARCH
(2022)
Review
Multidisciplinary Sciences
Se-Min Kim, Tony Yuen, Jameel Iqbal, Mishaela R. Rubin, Mone Zaidi
Summary: The NO-cGMP-PKG pathway is crucial for skeletal homeostasis, but long-term use of NO is limited by off-target effects. Inhibiting cGMP-specific phosphodiesterase to promote the anabolic signal offers a potential treatment for osteoporosis with PDE5A inhibitors. Further research is needed to investigate the specific effects of PDE5A inhibition on bone cells and the pathophysiological changes in skeletal PDE5A expression.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Iraida Sharina, Karina Lezgyieva, Yekaterina Krutsenko, Emil Martin
Summary: This study characterized a rare sGC variant with reduced cGMP-forming activity, high susceptibility to oxidative stress, and diminished protein stability. These deficiencies contribute to the severity of moyamoya disease and achalasia symptoms in carriers of this variant.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Dominique E. Williams, Natasha M. Nesbitt, Sandhya Muralidharan, Sajjad Hossain, Elizabeth M. Boon
Summary: Transitions between motile and biofilm lifestyles are regulated by H-NOX, a key regulator of bacterial communal behaviors. In Agrobacterium vitis S4, avH-NOX binds to and regulates the activity of avHaCE, a predicted bifunctional cyclic di-GMP metabolizing enzyme. avH-NOX enhances cyclic di-GMP degradation to reduce biofilm formation in response to NO in A. vitis.
Review
Biochemistry & Molecular Biology
Elizabeth C. Wittenborn, Michael A. Marletta
Summary: sGC functions as the prototypical nitric oxide receptor in humans and other higher eukaryotes, transducing NO signals into cGMP for various physiological effects. Recent advancements in cryo-EM have allowed for the visualization of full-length sGC structures, providing valuable insights into sGC activation mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Yuliy Y. Chirkov, Thanh H. Nguyen, John D. Horowitz
Summary: During normal aging, there is an increased tendency towards platelet-rich thrombus formation, which is mediated by decreased platelet responsiveness to nitric oxide (NO) and prostacyclin (PGI(2)), both of which have anti-aggregatory effects. This reduced responsiveness is primarily caused by impairment of guanylate cyclase and adenylate cyclase-based signaling due to oxidative stress. Platelet desensitization to these autacoids is a negative prognostic marker in patients with ischemic heart disease and may contribute to higher thrombo-embolic risk in heart failure patients. Additionally, patients with platelet resistance to PGI(2) are also unresponsive to ADP receptor antagonist therapy. Impaired anti-aggregatory homeostasis is also associated with diabetes and aortic valve disease, apart from ischemia. This review examines the correlation between impaired platelet cyclic nucleotide signaling and the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses potential therapeutic strategies to target this abnormality.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Neurosciences
James B. Ames
Summary: This article explores the role of Retinal membrane guanylate cyclases in visual recovery and their interactions with regulatory proteins, as well as how mutations linked to inherited blindness can disrupt the regulation of cyclase activity.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Gang Wu, Iraida Sharina, Emil Martin
Summary: Nitric oxide (NO), carbon monoxide (CO), oxygen (O-2), and hydrogen sulfide (H2S) are gaseous molecules that play important roles in the physiology and pathophysiology of eukaryotes. Soluble guanylyl cyclase (sGC), a hemoprotein, acts as a sensor and transducer for these gases, as well as a transporter.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Physiology
Kulwant S. Aulak, Sami Al Abdi, Ling Li, Jack S. Crabb, Arnab Ghosh, Belinda Willard, Dennis J. Stuehr, John W. Crabb, Raed A. Dweik, Adriano R. Tonelli
Summary: Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with great heterogeneity in treatment response and systemic involvement, despite most of its pathology being observed in the lung. Platelets from IPAH patients exhibit characteristic metabolic shifts and activation defects, as well as abnormalities in prostacyclin and nitric oxide pathways. These findings suggest potential targets for therapy, with variations in soluble guanylate cyclase levels showing implications for personalized treatment in IPAH patients. Platelets may provide informative mechanistic insights ex vivo to guide therapeutic decisions in IPAH.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Arnab Ghosh, Cynthia J. Koziol-White, William F. Jester, Serpil C. Erzurum, Kewal Asosingh, Reynold A. Panettieri, Dennis J. Stuehr
Summary: The study revealed that severe asthmatics have inherent defects in sGC in their airway smooth muscle, leading to impaired NO-sGC-cGMP signaling. This dysfunction is associated with changes in cell redox enzymes that impact sGC maturation and function.
Article
Biochemistry & Molecular Biology
Maria Peleli, Paraskevas Zampas, Andreas Papapetropoulos
Summary: Hydrogen sulfide plays crucial roles in the kidney by exerting antioxidant, cytoprotective, vasodilatory effects, among others, impacting renal function and diseases significantly. Lower H2S levels are associated with various renal pathologies, highlighting the importance of uncovering its molecular targets for potential therapeutic interventions in renal diseases. Further studies on H2S in the kidney, including mapping expression patterns of related enzymes and generating cell-specific knockout models, will provide valuable insights for developing novel, more effective strategies for treating renal diseases.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Biochemistry & Molecular Biology
Blair Tupta, Eric Stuehr, Mamta P. Sumi, Elizabeth A. Sweeny, Brandon Smith, Dennis J. Stuehr, Arnab Ghosh
Summary: This study reveals the important role of GAPDH in the maturation of myoglobin and hemoglobins by regulating the formation of sGC alpha1 beta1 heterodimer, iron provision, and the expression of GAPDH. These findings provide insights into the mechanisms of heme-maturation in globins.
Article
Multidisciplinary Sciences
Yue Dai, Emily M. Faul, Arnab Ghosh, Dennis J. Stuehr
Summary: Nitric oxide (NO) signaling in biology relies on its activating cyclic guanosine monophosphate (cGMP) production by the NO receptor soluble guanylyl cyclase (sGC). Physiological levels of NO trigger the mobilization of heme to immature sGC, leading to the construction of functional sGC heterodimers and increased active sGC levels. The process involves glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-heme complexes and the chaperone hsp90.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Rosemary Westcott, Natalie Chung, Arnab Ghosh, Lisa Ferguson, William Bingaman, Imad M. Najm, Chaitali Ghosh
Summary: This study reveals that the different isoforms of glucocorticoid receptor (GR) at the blood-brain barrier (BBB) play important roles in the pathogenesis of drug-resistant epilepsy with focal cortical dysplasia (FCD). The expression of GR beta is upregulated in dysplastic brain tissue and is associated with age and gender. The findings suggest that GR beta could serve as a potential biomarker and therapeutic target for dysplasia in epilepsy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Physiology
Giuseppe Cirino, Csaba Szabo, Andreas Papapetropoulos
Summary: This article provides a comprehensive review of the role of hydrogen sulfide (H2S) as an endogenous regulator in various physiological functions. It discusses the regulation, degradation, and elimination pathways of H2S enzymes, as well as the interactions between H2S and other endogenous molecules. Additionally, it outlines the biological targets, signaling pathways, and effects of H2S on cellular bioenergetics and metabolism. The article also reviews the available tools for studying H2S physiology and highlights the wide array of roles H2S plays in the regulation of organ functions.
PHYSIOLOGICAL REVIEWS
(2023)
Article
Cell Biology
Mamta P. Sumi, Arnab Ghosh
Summary: The maturation of hemeprotein is essential for cellular function, and studies have shown that Hsp90 plays a key role in driving heme maturation. It connects globin maturation to the NO-sGC signal pathway, which is significant for therapeutic intervention, particularly in aggressive cancer cells. The combination of sGC activators/stimulators and specific Hsp90 inhibitors may provide better therapeutic options.
Article
Biochemistry & Molecular Biology
Arnab Ghosh, Mamta P. Sumi, Blair Tupta, Toshihiro Okamoto, Kulwant Aulak, Masato Tsutsui, Hiroaki Shimokawa, Serpil C. Erzurum, Dennis J. Stuehr
Summary: Low doses of NO have a dual effect on the maturation of key hemeproteins, acting both to promote and inhibit heme-insertion, while high NO doses inhibit heme-insertion. This phenomenon is observed in soluble guanylyl cyclase, globins, nitric oxide synthases, and Myeloperoxidase. The effects of low NO on hemeprotein maturation require the presence of the NO-sGC-cGMP signal pathway.
Article
Cell Biology
Mamta P. Sumi, Blair Tupta, Arnab Ghosh
Summary: NO acts as a vasodilator and triggers heme insertion into hemoglobin and myoglobin. This process is dose-dependent, with better efficiency at lower doses. It involves both transcriptional and translational events.
Article
Cell & Tissue Engineering
Panagiota Siatra, Giannis Vatsellas, Athanasia Chatzianastasiou, Evangelos Balafas, Theodora Manolakou, Andreas Papapetropoulos, Anna Agapaki, Eleni-Taxiarchia Mouchtouri, Prashant J. Ruchaya, Artemis G. Korovesi, Manolis Mavroidis, Dimitrios Thanos, Dimitris Beis, Ioannis Kokkinopoulos
Summary: Heart transplantation is the only cure for patients with heart failure, but it is limited by donor shortage, immunosuppression and economic costs. Therefore, there is an urgent need to identify cell populations capable of cardiac regeneration. Recent studies have identified a Tbx5-expressing precursor cell population in the injured adult mammalian heart that shows potential for cardiomyocyte regeneration.
NPJ REGENERATIVE MEDICINE
(2023)
Editorial Material
Pharmacology & Pharmacy
Andreas Papapetropoulos, Steve P. H. Alexander, Miriam Cortese-Krott, Dave A. Kendall, Kirill Martemyanov, Claudio Mauro, Reynold A. A. Panettieri Jr, Hemal H. H. Patel, Rainer Schulz, Barbara Stefanska, Gary J. Stephens, Mauro M. Teixeira, Nathalie Vergnolle, Xin Joy Wang, Peter Ferdinandy
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mamta P. Sumi, Blair Tupta, Sanjoy Roychowdhury, Suzy Comhair, Kewal Asosingh, Dennis J. Stuehr, Serpil C. Erzurum, Arnab Ghosh
Summary: This study discovered that hemoglobin in lung epithelial cells can protect soluble guanylyl cyclase in smooth muscles from excessive nitric oxide. However, in patients with asthma or chronic obstructive pulmonary disease, lung epithelial hemoglobin may be unable to scavenge nitric oxide due to a lack of heme.
Article
Biochemical Research Methods
Antonia Katsouda, Dimitrios Valakos, Giannis Vatsellas, Dimitris Thanos, Andreas Papapetropoulos
Summary: This article presents a ChIP protocol for murine inguinal white adipose tissue, including steps for sample processing and analysis.
Article
Biochemistry & Molecular Biology
Aikaterini I. Argyriou, Garyfallia I. Makrynitsa, Georgios Dalkas, Dimitra A. Georgopoulou, Konstantinos Salagiannis, Vassiliki Vazoura, Andreas Papapetropoulos, Stavros Topouzis, Georgios A. Spyroulias
Summary: The gasotransmitter nitric oxide plays a critical role in endogenous regulation by activating sGC to produce cGMP. Drugs known as sGC activators aim to stabilize sGC activity by replacing oxidized heme. Through NMR, this study uncovers the dynamic interaction between sGC activators and the H-NOX domain, shedding light on the mechanism of action.
CURRENT RESEARCH IN STRUCTURAL BIOLOGY
(2021)