Redox Mechanisms Influencing cGMP Signaling in Pulmonary Vascular Physiology and Pathophysiology

Patel, Dhara; Lakhkar, Anand; Wolin, Michael S.

doi:10.1007/978-3-319-63245-2_13

Cited by 8 publications

(3 citation statements)

References 64 publications

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“…While the oxidation of heme sGC under pathophysiological conditions and its association with enhanced sGC activation by sGC activators under these conditions are well documented, most of the hypothesized relationships between the function of ferrochelatase in heme biosynthesis and sGC regulation remain to be investigated (Patel et al 2017). Mitochondrial heme biosynthesis is an important factor in controlling the expression and function of sGC and systems influencing superoxide generation and actions.…”

mentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

132

149

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When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

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mentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

132

149

View full text Add to dashboard Cite

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“…NO elevates cyclic GMP (cGMP) concentrations in VSM cells by stimulation of soluble guanylyl cyclase (sGC) activity. Elevated cGMP levels activate protein kinase G (PKG), which diminishes Ca 2+ levels in the cell through multiple mechanisms, and consequently vasorelaxation is induced (14). Reduced availability and/or responsiveness to NO hinders the vasculature to accustom to constriction/dilatation in response to blood flow changes (15).…”

Section: Introductionmentioning

confidence: 99%

Estrogen Contributions to Microvascular Dysfunction Evolving to Heart Failure With Preserved Ejection Fraction

et al. 2019

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Heart failure with preserved ejection fraction (HFpEF) is a syndrome involving microvascular dysfunction. No treatment is available yet and as the HFpEF patient group is expanding due to the aging population, more knowledge on dysfunction of the cardiac microvasculature is required. Endothelial dysfunction, impaired angiogenesis, (perivascular) fibrosis and the pruning of capillaries (rarefaction) may all contribute to microvascular dysfunction in the heart and other organs, e.g., the kidneys. The HFpEF patient group consists mainly of post-menopausal women and female sex itself is a risk factor for this syndrome. This may point toward a role of estrogen depletion after menopause in the development of HFpEF. Estrogens favor the ratio of vasodilating over vasoconstricting factors, which results in an overall lower blood pressure in women than in men. Furthermore, estrogens improve angiogenic capacity and attenuate (perivascular) fibrosis formation. Therefore, we hypothesize that the drop of estrogen levels after menopause contributes to myocardial microvascular dysfunction and renders post-menopausal women more vulnerable for heart diseases that involve the microvasculature. This review provides a detailed summary of molecular targets of estrogen, which might guide future research and treatment options.

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“…Beyond the physiological role of NO• in exercise training, we cannot exclude the key participation of the vasodilator factor in the redox metabolism of lungs [ 39 ]. Bleo notoriously generates reactive oxygen and nitrogen species (ROS/RNS) by chelating redox-active ferrous ions (complex [Bleo:Fe 2+ ]), then reacting with molecular oxygen (O 2 ) to form the highly reactive low-spin ferric hydroperoxide [Bleo:Fe 2+ -OOH] [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Exercise Improves Lung Inflammation, but Not Lung Remodeling and Mechanics in a Model of Bleomycin-Induced Lung Fibrosis

El-Mafarjeh

Martins

Probst

et al. 2020

Oxidative Medicine and Cellular Longevity

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Introduction. Moderate aerobic exercise training accelerates the resolution of lung fibrosis in a model of bleomycin-induced pulmonary fibrosis. However, whether it can inhibit the development of lung fibrosis is unknown. Materials and Methods. C57Bl/6 mice were distributed into four groups: Control (Co), Exercise (Exe), Bleomycin (Bleo), and Bleomycin+Exercise (Bleo+Exe). A single bleomycin dose (1.5 UI/kg) was administered orotracheally and treadmill exercise started in the same day, enduring for 4 weeks, 5x/week, 60 minutes/session, at moderate intensity. Lung mechanics, systemic and pulmonary inflammation, and lung remodeling were evaluated. Lung homogenates were used to evaluate the antioxidant status. Results. Total cells, macrophages, lymphocytes, and neutrophils numbers, in agreement with IL-6 levels, were higher in the BAL and serum of Bleo group, compared to other groups. In addition, lung levels of LTB4 in Bleo were higher than other groups, whereas SOD activity and nitric oxide levels in exercised groups (Exe and Exe+Bleo) compared to the Bleo group. Lung GPX activity was lower in Bleo and Exe+Bleo groups compared to others. Exe and Exe+Bleo groups also showed higher IL-10 expression by lung macrophages than other groups, whereas TGF-β expression was higher in Exe, Bleo, and Exe+Bleo groups compared to control. CCR7 expression was induced only in the Exe group. However, exercise did not improve lung remodeling and mechanics, or serum and pulmonary levels of VEGF, IGF-1, and TGF-β. Conclusion. Aerobic exercise training initiated concomitantly with induction of pulmonary fibrosis reduces lung and systemic inflammation but fails to inhibit lung fibrosis and mechanics impairment.

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Redox Mechanisms Influencing cGMP Signaling in Pulmonary Vascular Physiology and Pathophysiology

Cited by 8 publications

References 64 publications

Soluble Guanylate Cyclase Stimulators and Activators

Soluble Guanylate Cyclase Stimulators and Activators

Estrogen Contributions to Microvascular Dysfunction Evolving to Heart Failure With Preserved Ejection Fraction

Exercise Improves Lung Inflammation, but Not Lung Remodeling and Mechanics in a Model of Bleomycin-Induced Lung Fibrosis

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