Angiotensin-Converting Enzyme 2 in the Rostral Ventrolateral Medulla Regulates Cholinergic Signaling and Cardiovascular and Sympathetic Responses in Hypertensive Rats

Deng, Yu; Tan, Xing; Li, Miaoling; Wang, Weizhong; Wang, Yang-Kai

doi:10.1007/s12264-018-0298-3

Cited by 19 publications

(18 citation statements)

References 63 publications

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“…The negatively correlated genes were involved with synaptic transmission and signaling. ACE2 overexpression in the brain attenuates the enhanced cholinergic synaptic transmission in spontaneously hypertensive rats (Deng et al, 2019). Therefore, the mechanism of ACE2 in attenuating vasoconstriction may not only involve the conversion of Ang II to Ang (1-7), but also the inhibition synaptic transmission.…”

Section: Discussionmentioning

confidence: 99%

Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database

Yang

2020

Front. Genet.

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Background: The coronavirus disease 2019 (COVID-19) has become a worldwide public health crisis. At present, there are no effective antiviral drugs to treat COVID-19. Although some vaccines have been developed, late-stage clinical trials that allow licensure by regulatory agencies are still needed. Previous reports have indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV are highly homologous and both use angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells, and SARS-CoV infection reduces the ACE2 expression in the lung. Therefore, the analysis of genes co-expressed with ACE2 in the lung may uncover the underlying mechanism of COVID-19. Finally, we used the Connectivity map (Cmap) database to search for candidate drugs using transcriptome profiles of patients with COVID-19. Method: Based on the differentially expressed genes (DEGs), indicated by the expression of RNAs isolated from bronchoalveolar lavage fluid (BALF) cells of patients with COVID-19, we performed functional enrichment analysis and hub gene cluster analysis. Furthermore, we identified genes co-expressed with ACE2 in healthy lung samples and analyzed the significant genes. Additionally, to identify several candidate drugs for the treatment of COVID-19, we queried Cmap using DEGs and genes co-expressed with ACE2. Results and Conclusion: The up-regulated genes in the BALF cells of patients with COVID-19 are related to viral mRNA translation. The down-regulated genes are related to immune response functions. Genes positively correlated with ACE2 are related to immune defense and those negatively correlated are enriched in synaptic transmission functions. The results reflected prosperous viral proliferation and immune dysfunction in patients. Furthermore, ACE2 may not only mediate viral entrance, but also play an important role in immune defense. By using Cmap with transcriptome profiles of patients with COVID-19, we identified candidate drugs for the treatment of COVID-19, such as amantadine and acyclovir.

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Section: Discussionmentioning

confidence: 99%

Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database

Yang

2020

Front. Genet.

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“…These regions, which are known to also express various types of nAChRs (Dani and Bertrand, 2007), are putative sites for primary infection with COVID19 in the human brain. Interactions between nAChRs and ACE2 have been studied in several of these regions including the ventrolateral medulla (Deng et al, 2019), and smoking may lead to enhanced viral infection through the ability of nicotine to upregulate nAChRs in regions such as the lungs (Plummer et al, 2005;Thorgeirsson et al, 2008;Changeux, 2010). In this case, upregulation of nAChRs in either/both neurons and astrocytes could promote greater viral entry and replication through augmented ACE2 expression in the cell ( Fig.…”

Section: Significance Statementmentioning

confidence: 99%

Does COVID19 Infect the Brain? If So, Smokers Might Be at a Higher Risk

Kabbani¹,

Olds²

2020

Mol Pharmacol

126

114

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COVID19 is a devastating global pandemic with epicenters in China, Italy, Spain, and now the United States. While the majority of infected cases appear mild, in some cases, individuals present serious cardiorespiratory complications with possible long-term Fig. 2. Mechanisms of ACE2 entry and COVID19 infection in neural cells. (A) A role for nicotine-associated upregulation of nAChRs in ACE2 expressing astrocytes and neurons. Based on published findings, upregulation of nAChRs can also increase ACE2 cell surface expression, thereby enhancing viral entry and infection. (B) A putative clinical timeline for progression of COVID19 into the brain. Coronavirus in the Brain and the Impact of Smoking

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“…The activation of various neurogenic pathways, such as stimulation of the sympathetic nervous system (SNS), mediates not only short-term increases in blood pressure (BP), but also the elevation of chronic BP in response to specific stresses [2]. The sympathetic outflow is controlled by key cerebral nuclei and neural circuits in the central nervous system (CNS), predominantly the rostral ventrolateral medulla (RVLM) [3][4][5], the nucleus tractus solitarius, and the hypothalamic paraventricular nucleus (PVN), all of which are associated with the activities of the autonomic nervous system [2].…”

Section: Introductionmentioning

confidence: 99%

Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

Zhang

Ooi

et al. 2020

Neurosci. Bull.

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Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla (RVLM) have been implicated in stress-induced hypertension (SIH). Prorenin, a member of the brain renin-angiotensin system (RAS), can directly activate microglia. The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats. Rats were subjected to intermittent electric foot-shocks plus noise, this stress was administered for 2 h twice daily for 15 consecutive days, and mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were monitored. The results showed that MAP and RSNA were augmented, and this paralleled increased pro-inflammatory phenotype (M1) switching. Prorenin and its receptor (PRR) expression and the NLR family pyrin domain containing 3 (NLRP3) activation were increased in RVLM of SIH rats. In addition, PLX5622 (a microglial depletion agent), MCC950 (a NLRP3 inhibitor), and/or PRO20 (a (Pro)renin receptor antagonist) had antihypertensive effects in the rats. The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622. Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in proreninstimulated microglia. Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation, while MCC950 decreased the M1 polarization. In conclusion, upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH, mediated by activation of the microglia-derived NLRP3 inflammasome. The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.

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Angiotensin-Converting Enzyme 2 in the Rostral Ventrolateral Medulla Regulates Cholinergic Signaling and Cardiovascular and Sympathetic Responses in Hypertensive Rats

Cited by 19 publications

References 63 publications

Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database

Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database

Does COVID19 Infect the Brain? If So, Smokers Might Be at a Higher Risk

Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

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