MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2

Zhang, Ruifeng; Su, Hua; Ma, Xiaochun; Xu, Xiaoling; Liang, Li; Ma, Guofeng; Shi, Liuhong

doi:10.1152/ajplung.00387.2018

Cited by 59 publications

(43 citation statements)

References 47 publications

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“…Interestingly very recently, Bunyavanich et al [19] showed agedependent expression of ACE2 gene in nasal epithelium, highlighting that the different levels of ACE2 expression may be the reason for a lower incidence of COVID-19 in children. Several studies have shown that ACE2 gene undergoes the action of at least four miRNAs: miR-200c, let-7b, miR-1246, and miR-125b [20][21][22][23]. Polymorphisms within genes coding for these miRNAs could be of great help with regards to investigations on the regulation of ACE2 gene expression and the possible significance of variations in further more in depth studies.…”

Section: Discussionmentioning

confidence: 99%

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

et al. 2020

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Background Coronaviruses (CoV) are a large family of viruses that are common in humans and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East respiratory syndrome (MERS-CoV), the severe acute respiratory syndrome corona virus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Several studies suggested that genetic variants in the ACE2 gene may influence the host susceptibility or resistance to SARS-CoV-2 infection according to the functional role of ACE2 in human pathophysiology. However, many of these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 131 Italian unrelated individuals clinically diagnosed with COVID-19 and in an Italian control population, to evaluate a possible allelic association with COVID-19, by direct DNA analysis. Methods As a pilot study, we analyzed, by whole-exome sequencing, genetic variants of ACE2 gene in 131 DNA samples of COVID-19 patients hospitalized at Tor Vergata University Hospital and at Bambino Gesù Children’s Hospital, Rome. We used a large control group consisting of 1000 individuals (500 males and 500 females). Results We identified three different germline variants: one intronic c.439+4G>A and two missense c.1888G>C p.(Asp630His) and c.2158A>G p.(Asn720Asp) in a total of 131 patients with a similar frequency in male and female. Thus far, only the c.1888G>C p.(Asp630His) variant shows a statistically different frequency compared to the ethnically matched populations. Therefore, further studies are needed in larger cohorts, since it was found only in one heterozygous COVID-19 patient. Conclusions Our results suggest that there is no strong evidence, in our cohort, of consistent association of ACE2 variants with COVID-19 severity. We might speculate that rare susceptibility/resistant alleles could be located in the non-coding regions of the ACE2 gene, known to play a role in regulation of the gene activity.

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Section: Discussionmentioning

confidence: 99%

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

et al. 2020

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“…Later, with the elevation of the hypoxia-inducible factor-1α (HIF-1α), the expression of ACE, the target gene of HIF-1α, increased accompanied by decrease of ACE2 [54]. Animal experiments demonstrated that similar regulation by HIF-1α on ACE2 level, possibly via miRNA let-7b after hypoxia in rats [55]. These results indicated that hypoxia and the cellular adaptation to hypoxia could profoundly induce the fluctuation of ACE2 in the lungs.…”

Section: Ace2 and Pulmonary Diseasesmentioning

confidence: 92%

Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor

Wei

et al. 2020

Pharmacological Research

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The renin-angiotensin system (RAS) is crucial for the physiology and pathology of all the organs. Angiotensinconverting enzyme 2 (ACE2) maintains the homeostasis of RAS as a negative regulator. Recently, ACE2 was identified as the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus that is causing the pandemic of Coronavirus disease 2019 (COVID-19). Since SARS-CoV-2 must bind with ACE2 before entering the host cells in humans, the distribution and expression of ACE2 may be critical for the target organ of the SARS-CoV-2 infection. Moreover, accumulating evidence has demonstrated the implication of ACE2 in the pathological progression in tissue injury and several chronic diseases, ACE2 may also be essential in the progression and clinical outcomes of COVID-19. Therefore, we summarized the expression and activity of ACE2 in various physiological and pathological conditions, and discussed its potential implication in the susceptibility of SARS-CoV-2 infection and the progression and prognosis of COVID-19 patients in the current review.

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“…Interestingly, previous evidence obtained from a study on SARS-CoV shows that HIF-1α may transcriptionally target all the proteins controlling cell entry of SARS-CoV-2, i.e., ACE, ACE2, TMPRSS2, and ADAM17 [30]. It was further demonstrated in a model of hypoxic pulmonary hypertension that HIF-1α exerts its inhibitory effect on ACE2 through microRNA let-7b, which directly targets the coding sequence of ACE2 [31]. It is postulated from previous studies under other nonviral conditions that HIF-1α also upregulates expression of ADAM17, which cleaves ACE2 from the alveolocyte surface and consequently may shut down the cell entry gates for SARS-CoV-2 [32,33].…”

Section: Ace2 and Tmprss2 In Sars-cov-2 Cell Entry: Potential Targetsmentioning

confidence: 97%

Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets

et al. 2020

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The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called "hypoxic conditioning" to activate HIF-1αinduced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.

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MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2

Cited by 59 publications

References 47 publications

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor

Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets

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