Soluble guanylate cyclase activator <scp>BAY</scp> 54–6544 improves vasomotor function and survival in an accelerated ageing mouse model

Ataabadi, Ehsan Ataei; Golshiri, Keivan; Jüttner, Annika A.; Vries, René de; Berg-Garrelds, I. van den; Nagtzaam, Nicole M. A.; Khan, Hina; Leijten, Frank; Brandt, Renata M. C.; Dik, Willem A.; Pluijm, Ingrid van der; Danser, A.H. Jan; Sandner, Peter; Roks, Anton J.M.

doi:10.1111/acel.13683

Cited by 9 publications

(4 citation statements)

References 61 publications

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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%

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%

Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study

et al. 2023

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“…The molecular mechanisms behind the biphasic effect of HO on the expression of these genes in HDLECs are unclear and require further study. In addition to reflecting the oxidative stress status of a cell, HO1 and NQO1 have several vasculoprotective effects [ 83 , 84 , 85 , 86 ]. Therefore, our finding of increased HO1 and NQO1 expression in HDLECs suggests that these cells are under oxidative stress following HO exposure, and they upregulate HO1 and NQO1 expression as an adaptive response to mitigate the effects of HO.…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia Disrupts Lung Lymphatic Homeostasis in Neonatal Mice

et al. 2023

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Inflammation causes bronchopulmonary dysplasia (BPD), a common lung disease of preterm infants. One reason this disease lacks specific therapies is the paucity of information on the mechanisms regulating inflammation in developing lungs. We address this gap by characterizing the lymphatic phenotype in an experimental BPD model because lymphatics are major regulators of immune homeostasis. We hypothesized that hyperoxia (HO), a major risk factor for experimental and human BPD, disrupts lymphatic endothelial homeostasis using neonatal mice and human dermal lymphatic endothelial cells (HDLECs). Exposure to 70% O2 for 24–72 h decreased the expression of prospero homeobox 1 (Prox1) and vascular endothelial growth factor c (Vegf-c) and increased the expression of heme oxygenase 1 and NAD(P)H dehydrogenase [quinone]1 in HDLECs, and reduced their tubule formation ability. Next, we determined Prox1 and Vegf-c mRNA levels on postnatal days (P) 7 and 14 in neonatal murine lungs. The mRNA levels of these genes increased from P7 to P14, and 70% O2 exposure for 14 d (HO) attenuated this physiological increase in pro-lymphatic factors. Further, HO exposure decreased VEGFR3+ and podoplanin+ lymphatic vessel density and lymphatic function in neonatal murine lungs. Collectively, our results validate the hypothesis that HO disrupts lymphatic endothelial homeostasis.

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“…Confirming the above, studies in animal models have revealed that vascular aging is earlier the more some of the mechanisms that regulate the response to vasomodulating substances are altered: in knockout animals for some genes involved in nuclear DNA damage repair mechanisms of vascular smooth muscle cells, nonatherosclerotic decay was seen due to altered endothelial responses [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 94%

Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases

Pacinella

Ciaccio

Tuttolomondo

2022

IJMS

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Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a diriment role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above. Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.

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Soluble guanylate cyclase activator BAY 54–6544 improves vasomotor function and survival in an accelerated ageing mouse model

Cited by 9 publications

References 61 publications

Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study

Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study

Hyperoxia Disrupts Lung Lymphatic Homeostasis in Neonatal Mice

Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases

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