Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice

Wood, Katherine C.; Durgin, Brittany G; Schmidt, Heidi M.; Hahn, Scott; Baust, Jeffrey; Bachman, Timothy N.; Vitturi, Darío A.; Ghosh, Samit; Ofori-Acquah, Solomon Fiifi; Mora, Ana L.; Gladwin, Mark T.; Straub, Adam C.

doi:10.1182/bloodadvances.2019000621

Cited by 13 publications

(12 citation statements)

References 59 publications

(85 reference statements)

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“…Experiments with the purified proteins showed that CYB5R3 was able to reduce the sGC ferric heme, albeit slowly, in a reaction that depended on NADPH and a direct protein–protein interaction ( 93 ). In a mouse model of sickle cell disease, CYB5R3 knockdown also enhanced the development of NO insensitivity of vascular sGC ( 121 ). Together, these findings argue that sGC heme oxidation occurs in oxidative or inflammatory settings and that heme reduction mediated by CYB5R3 is functionally significant for sGC recovery of function.…”

Section: Recovery Of Inactive Sgcmentioning

confidence: 99%

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Stuehr

Misra

Dai

et al. 2021

Journal of Biological Chemistry

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Soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO); sGC thereby acts as an amplifier in NO-driven biological signaling cascades. Because sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production, boosting sGC activity and preventing or reversing sGC inactivation are important therapeutic and pharmacologic goals. Work over the last two decades is uncovering the processes by which sGC matures to become functional, how sGC is inactivated, and how sGC is rescued from damage. A diverse group of small molecules and proteins have been implicated in these processes, including NO itself, reactive oxygen species, cellular heme, cell chaperone Hsp90, and various redox enzymes as well as pharmacologic sGC agonists. This review highlights their participation and provides an update on the processes that enable sGC maturation, drive its inactivation, or assist in its recovery in various settings within the cell, in hopes of reaching a better understanding of how sGC function is regulated in health and disease.

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Section: Recovery Of Inactive Sgcmentioning

confidence: 99%

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Stuehr

Misra

Dai

et al. 2021

Journal of Biological Chemistry

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“…1 ). Recent evidence has shown that oxidative stress associated with many cardiopulmonary diseases shifts intracellular native sGC levels towards the apo-sGC form [ 47 , 48 ], providing the rationale for sGC activators [ 49 – 52 ] in cardiopulmonary diseases and PH.…”

Section: Discussionmentioning

confidence: 99%

“…Results show percentage changes versus vehicle-treated control animals as mean ± SEM out of three or four experiments. BP mean blood pressure, PAP mean pulmonary arterial pressure, SEM standard error of the mean sGC levels towards the apo-sGC form [47,48], providing the rationale for sGC activators [49][50][51][52] in cardiopulmonary diseases and PH.…”

Section: Discussionmentioning

confidence: 99%

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC

et al. 2022

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Background Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential. Methods We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592). Results Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model. Conclusion Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

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“…CYB5R3 supports NO-responsive sGC by reducing its ferric heme to ferrous [ 32 ]. When CYB5R3 expression was knocked down in cells or in mice, their sGC became more susceptible to oxidative stressors causing NO-insensitivity and led to a greater BAY-60 activation response [ 45 ]. In our study, we found a strong correlation exists between low levels of CYB5R3 expression and sGC dysfunction in the HASMC lines and lung tissues.…”

Section: Discussionmentioning

confidence: 99%

An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling

et al. 2021

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A subset of asthmatics develop a severe form of the disease whose etiology involves airway inflammation along with inherent drivers that remain ill-defined. To address this, we studied human airway smooth muscle cells (HASMC), whose relaxation drives airway bronchodilation and whose dysfunction contributes to airway obstruction and hypersensitivity in severe asthma. Because HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway, we questioned if HASMC from severe asthma donors might possess inherent defects in their sGC or in redox enzymes that support sGC function. We analyzed HASMC primary lines derived from 17 severe asthma and 16 normal donors and corresponding lung tissue samples regarding sGC activation by NO or by pharmacologic agonists, and also determined expression levels of sGC α1 and β1 subunits, supporting redox enzymes, and related proteins. We found a majority of the severe asthma donor HASMC (12/17) and lung samples primarily expressed a dysfunctional sGC that was NO-unresponsive and had low heterodimer content and high Hsp90 association. This sGC phenotype correlated with lower expression levels of the supporting redox enzymes cytochrome b 5 reductase, catalase, and thioredoxin-1, and higher expression of heme oxygenases 1 and 2. Together, our work reveals that severe asthmatics are predisposed toward defective NO-sGC-cGMP signaling in their airway smooth muscle due to an inherent sGC dysfunction, which in turn is associated with inherent changes in the cell redox enzymes that impact sGC maturation and function.

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Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice

Abstract: Key Points Vascular SMC CYB5R3 delays development of SCD-associated PH in mice. PH in SCD can exist in mice by 5 weeks of age when SMC CYB5R3 protein is deficient.

Cited by 13 publications

References 59 publications

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC

An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling

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