Factors influencing the soluble guanylate cyclase heme redox state in blood vessels

Tawa, Masashi; Okamura, Tomio

doi:10.1016/j.vph.2022.107023

Cited by 4 publications

(4 citation statements)

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“…NO deficiency related to older age could also result from increased oxidative stress leading to a dysfunctional NOS system [52]. Downstream signaling, namely, soluble guanyl cyclase (sGC), or other members of the cascade (such as PDE5) could also malfunction in older age [53][54][55][56][57][58]. We consider that this might be the most likely explanation for our findings, but this hypothesis requires further experimental evidence to be confirmed.…”

Section: Baseline Nitritementioning

confidence: 84%

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Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study

et al. 2023

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Nitric oxide (NO) (co)regulates many physiological processes in the body. Its short-lived free radicals force synthesis in situ and on-demand, without storage possibility. Local oxygen availability determines the origin of NO—either by synthesis by nitric oxide synthases (NOS) or by the reduction of nitrate to nitrite to NO by nitrate/nitrite reductases. The existence of nitrate reservoirs, mainly in skeletal muscle, assures the local and systemic availability of NO. Aging is accompanied by changes in metabolic pathways, leading to a decrease in NO availability. We explored age-related changes in various rat organs and tissues. We found differences in nitrate and nitrite contents in tissues of old and young rats at baseline levels, with nitrate levels being generally higher and nitrite levels being generally lower in old rats. However, there were no differences in the levels of nitrate-transporting proteins and nitrate reductase between old and young rats, with the exception of in the eye. Increased dietary nitrate led to significantly higher nitrate enrichment in the majority of old rat organs compared to young rats, suggesting that the nitrate reduction pathway is not affected by aging. We hypothesize that age-related NO accessibility changes originate either from the NOS pathway or from changes in NO downstream signaling (sGC/PDE5). Both possibilities need further investigation.

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Section: Baseline Nitritementioning

confidence: 84%

“…Equally importantly, one could also hypothesize that additional changes in downstream signaling require consideration, especially at the level of soluble guanyl cyclase (sGC), which is susceptible to inactivation due to its heme oxidation and/or PDE5, which destroys cGMP [56].…”

Section: Summary and Hypothesismentioning

confidence: 99%

Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study

et al. 2023

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“…Once NO is released, this can be "scavenged" by the superoxide anion (O 2 − ) under conditions of oxidative stress, leading to the generation of peroxynitrite, an indirect modulator of impaired cellular energetics [58]. Finally, soluble guanylate cyclase is readily oxidised, with or without an associated loss of its haem moiety, resulting in the reduction in formation of cyclic guanosine monophosphate (cGMP), which mediates most biological effects of NO [59]. There is even some evidence that soluble guanylate cyclase, when subjected to oxidative stress, may lose its selectivity for the production of cGMP, instead generating the vasoconstrictor inosine phosphate [60].…”

Section: Coronary Microvascular Dysfunction: Can We Be More Precise?mentioning

confidence: 99%

“…In terms of the benefits from a clinical physiology point of view, the requisite processes need to include a re-evaluation of Gregg's phenomenon as a specifically microvascular therapeutic target [59]. Specifically, the concept that there may be an interaction between the coronary perfusion rate and myocardial contractile performance is of potential therapeutic interest in all of the conditions which have been discussed above.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Coronary “Microvascular Dysfunction”: Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics

Kei,

Singh,

Dautov

et al. 2023

IJMS

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Until recently, it has been generally held that stable angina pectoris (SAP) primarily reflects the presence of epicardial coronary artery stenoses due to atheromatous plaque(s), while acute myocardial infarction (AMI) results from thrombus formation on ruptured plaques. This concept is now challenged, especially by results of the ORBITA and ISCHEMIA trials, which showed that angioplasty/stenting does not substantially relieve SAP symptoms or prevent AMI or death in such patients. These disappointing outcomes serve to redirect attention towards anomalies of small coronary physiology. Recent studies suggest that coronary microvasculature is often both structurally and physiologically abnormal irrespective of the presence or absence of large coronary artery stenoses. Structural remodelling of the coronary microvasculature appears to be induced primarily by inflammation initiated by mast cell, platelet, and neutrophil activation, leading to erosion of the endothelial glycocalyx. This leads to the disruption of laminar flow and the facilitation of endothelial platelet interaction. Glycocalyx shedding has been implicated in the pathophysiology of coronary artery spasm, cardiovascular ageing, AMI, and viral vasculitis. Physiological dysfunction is closely linked to structural remodelling and occurs in most patients with myocardial ischemia, irrespective of the presence or absence of large-vessel stenoses. Dysfunction includes the impairment of platelet and vascular responsiveness to autocidal coronary vasodilators, such as nitric oxide, prostacyclin, and hydrogen sulphide, and predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation. These findings emphasise the need for new directions in medical therapeutics for patients with SAP, as well as a wide range of other cardiovascular disorders.

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