| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T118 |
0-332 |
Sentence |
denotes |
Similarly to hypoxic conditions, a strong correlation between the gene expression of ACE and that of ACE2 was also observed in human renal cortical biopsy specimen, suggesting a link between the two gene transcription, possibly related to the amount/excess of their substrates (Ang I and Ang II) and not exclusively to hypoxia [74]. |
| T119 |
333-693 |
Sentence |
denotes |
A link that tends to maintain the balance of ACE/ACE2 ratio, but that may be disrupted by ACE inhibitors (ACEIs) or by Ang II type 1 receptor blockers (ARBs) which both have been shown to upregulate ACE2 mRNA expression in left ventricle of Lewis rats, possibly through two different mechanisms involving upregulation of Ang (1–7) or Ang II, respectively [75]. |
| T120 |
694-959 |
Sentence |
denotes |
In this regard, in cardiac myocytes isolated from neonatal rats, Ang II significantly reduced ACE2 mRNA and its activity, effects blocked by ARBs, indicating that Ang II downregulates ACE2 expression/activity through an AT1R-dependent mechanism [76] (see Figure 1). |
| T121 |
960-1314 |
Sentence |
denotes |
Moreover, in both cardiac myocytes and rat aortic vascular smooth muscle cells, Ang (1–7) prevented the Ang II-mediated reduction in ACE2 mRNA, an effect blocked by a selective MasR antagonist, D-Ala7-Ang-(1–7) (also known as A779), indicating that Ang (1–7) downregulates Ang II/AT1R signalling through a MasR-dependent mechanism [76,77] (see Figure 1). |
| T122 |
1315-1658 |
Sentence |
denotes |
Therefore, Ang (1–7) (as well as ACEIs and ARBs), preventing Ang II-mediated ACE2 downregulation, shift the Ang peptide balance in favour of Ang II metabolisation by ACE2, which, in turn, leads to further production of Ang (1–7), finally sustaining ACE2 transcription, membrane protein expression and eventually shedding and systemic activity. |
| T123 |
1659-1870 |
Sentence |
denotes |
Altogether these observations indicate a complex interplay of regulation between the two arms of the RAS in which feedback mechanisms of reciprocal (ACE/ACE2) pathway inhibition are involved at different levels: |
| T124 |
1871-2058 |
Sentence |
denotes |
Ang II/AT1 receptor mediates a negative feedback signal on the ACE2 expression/activity and Ang (1–7)/MasR mediated a negative feedback signal on the AT1 receptor activity (see Figure 1). |
| T125 |
2059-2289 |
Sentence |
denotes |
These reciprocal inhibitions in some cases (e.g., hypoxia/SARS-CoV-2 infection) can give rise to positive feedback loops that markedly shift the balance between Ang II/AT1R and the antagonist Ang (1–7)/MasR pathway (see Figure 1). |
| T126 |
2290-2587 |
Sentence |
denotes |
For example, under hypoxic conditions both arms of the RAS are upregulated and the presence of SARS-CoV-2 can affect Ang (1–7)/Ang II balance (which might be further influenced by ACEI/ARBs) by shifting it in favour of an increased ACE2 systemic activity, Ang (1–7) production and MasR activation. |
| T127 |
2588-2803 |
Sentence |
denotes |
This, in turn, can lead to further ACE2 cell membrane expression (increasing the probability of viral entry), which, after ACE2 shedding by binding to spike-SARS-CoV-2, ultimately establish a positive feedback loop. |
