PKCβ and reactive oxygen species mediate enhanced pulmonary vasoconstrictor reactivity following chronic hypoxia in neonatal rats

Sheak, Joshua R.; Yan, Song; Weise-Cross, Laura; Ahmadian, Rosstin; Walker, Benjimen R.; Jernigan, Nikki L.; Resta, Thomas C.

doi:10.1152/ajpheart.00629.2019

Cited by 11 publications

(10 citation statements)

References 68 publications

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“…MitoSOX fluorescence intensity in hypoxic HPASMCs was increased, which was decreased after C75 incubation or shFAS infection (Figures 7(d) and 7(e) ). This is in line with the latest reports; Sheak et al reported PKC β and mitochondrial reactive oxygen species signaling to increase pulmonary vasoconstrictor reactivity in chronically hypoxic neonates [ 22 ]. Hang et al reported that hypoxia increased BPA levels of MitoSOX-detected superoxide and caused changes in NOX2 and SOD2 expression similar to COMP siRNA, and exogenous COMP (0.5 μ M) prevented the effects of hypoxia [ 23 ].…”

Section: Discussionsupporting

confidence: 92%

The Emerging Role of Fatty Acid Synthase in Hypoxia‐Induced Pulmonary Hypertensive Mouse Energy Metabolism

Hou

Chen

Zhao

et al. 2021

Oxidative Medicine and Cellular Longevity

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Aims. This study is aimed at examining whether fatty acid synthase (FAS) can regulate mitochondrial function in hypoxia-induced pulmonary arterial hypertension (PAH) and its related mechanism. Results. The expression of FAS significantly increased in the lung tissue of mice with hypoxia-induced PAH, and its pharmacological inhibition by C75 ameliorated right ventricle cardiac function as revealed by echocardiographic analysis. Based on transmission electron microscopy and Seahorse assays, the mitochondrial function of mice with hypoxia was abnormal but was partially reversed after C75 injection. In vitro studies also showed an increase in the expression of FAS in hypoxia-induced human pulmonary artery smooth muscle cells (HPASMCs), which could be attenuated by FAS shRNA as well as C75 treatment. Meanwhile, C75 treatment reversed hypoxia-induced oxidative stress and activated PI3K/AKT signaling. shRNA-mediated inhibition of FAS reduced its expression and oxidative stress levels and improved mitochondrial respiratory capacity and ATP levels of hypoxia-induced HPASMCs. Conclusions. Inhibition of FAS plays a crucial role in shielding mice from hypoxia-induced PAH, which was partially achieved through the activation of PI3K/AKT signaling, indicating that the inhibition of FAS may provide a potential future direction for reversing PAH in humans.

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Section: Discussionsupporting

confidence: 92%

The Emerging Role of Fatty Acid Synthase in Hypoxia‐Induced Pulmonary Hypertensive Mouse Energy Metabolism

Hou

Chen

Zhao

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Protein kinase C β (PRKCB) was also increased in individuals with higher DNA damage. ROS production is stimulated by PRKCB, thus leading to an increase in DNA damage, which can explain the association found in this study [ 68 , 69 ]. Others have demonstrated that PRKCB regulates cellular signaling pathways involved in the autophagic process [ 43 ].…”

Section: Discussionsupporting

confidence: 60%

DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents

et al. 2021

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Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents (n = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% ± 1.2 and cluster 2 = 13.8% ± 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 ± 1.6 mg/dL; 5.4 ± 1.3 mg/dL, p = 0.003) and EPA (0.6 ± 0.2 mg/dL; 0.5 ± 0.1 mg/dL, p < 0.001) presented increased expression of the proteins CDK8–CCNC, PIK3CA–PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8–CCNC, PIK3CA–PIK3R1, KYNU, and PRKCB.

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“…We find that in our case population, the risk-associated SNP found in PRKCB was found in 165 severe COVID-19 cases (penetrance = 20.2%), and was present in 45% of patients with cardiovascular disease and 51% of patients with hypertension. High levels of PKCβ result in increased vascular inflammation, endothelial dysfunction and oxidative stress, all of which have been found in patients with severe COVID-19 92,93 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Taylor¹,

Das²,

Pearson³

et al. 2020

Preprint

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BACKGROUND Epidemiological studies indicate that as many as 20% of individuals who test positive for COVID-19 develop severe symptoms that can require hospitalization. These symptoms include low platelet count, severe hypoxia, increased inflammatory cytokines and reduced glomerular filtration rate. Additionally, severe COVID-19 is associated with several chronic co-morbidities, including cardiovascular disease, hypertension and type 2 diabetes mellitus. The identification of genetic risk factors that impact differential host responses to SARS-CoV-2, resulting in the development of severe COVID-19, is important in gaining greater understanding into the biological mechanisms underpinning life-threatening responses to the virus. These insights could be used in the identification of high-risk individuals and for the development of treatment strategies for these patients. METHODS As of June 6, 2020, there were 976 patients who tested positive for COVID-19 and were hospitalized, indicating they had a severe response to SARS-CoV-2. There were however too few patients with a mild form of COVID-19 to use this cohort as our control population. Instead we used similar control criteria to our previous study looking at shared genetic risk factors between severe COVID-19 and sepsis, selecting controls who had not developed sepsis despite having maximum co-morbidity risk and exposure to sepsis-causing pathogens. RESULTS Using a combinatorial (high-order epistasis) analysis approach, we identified 68 protein-coding genes that were highly associated with severe COVID-19. At the time of analysis, nine of these genes have been linked to differential response to SARS-CoV-2. We also found many novel targets that are involved in key biological pathways associated with the development of severe COVID-19, including production of pro-inflammatory cytokines, endothelial cell dysfunction, lipid droplets, neurodegeneration and viral susceptibility factors. CONCLUSION The variants we found in genes relating to immune response pathways and cytokine production cascades, were in equal proportions across all severe COVID-19 patients, regardless of their co-morbidities. This suggests that such variants are not associated with any specific co-morbidity, but are common amongst patients who develop severe COVID-19. Among the 68 severe COVID-19 risk-associated genes, we found several druggable protein targets and pathways. Nine are targeted by drugs that have reached at least Phase I clinical trials, and a further eight have active chemical starting points for novel drug development. Several of these targets were particularly enriched in specific co-morbidities, providing insights into shared pathological mechanisms underlying both the development of severe COVID-19, ARDS and these predisposing co-morbidities. We can use these insights to identify patients who are at greatest risk of contracting severe COVID-19 and develop targeted therapeutic strategies for them, with the aim of improving disease burden and survival rates.

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PKCβ and reactive oxygen species mediate enhanced pulmonary vasoconstrictor reactivity following chronic hypoxia in neonatal rats

Cited by 11 publications

References 68 publications

The Emerging Role of Fatty Acid Synthase in Hypoxia‐Induced Pulmonary Hypertensive Mouse Energy Metabolism

The Emerging Role of Fatty Acid Synthase in Hypoxia‐Induced Pulmonary Hypertensive Mouse Energy Metabolism

DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

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