Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 microM; while at 100 microM the increase (129.74+/-3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARS-CoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells.
- MeSH
- angiotensin I metabolismus farmakologie MeSH
- angiotensin II metabolismus MeSH
- angiotensin konvertující enzym metabolismus MeSH
- angiotensin-konvertující enzym 2 metabolismus MeSH
- COVID-19 * MeSH
- glykoprotein S, koronavirus * MeSH
- inhibitory ACE MeSH
- lidé MeSH
- renin-angiotensin systém * MeSH
- SARS-CoV-2 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. METHODS: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined. RESULTS: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. CONCLUSION: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.
- MeSH
- albuminurie farmakoterapie MeSH
- angiotensin I metabolismus MeSH
- angiotensin II metabolismus MeSH
- časové faktory MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- hypertenze maligní chemicky indukované patofyziologie prevence a kontrola MeSH
- indoly MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- kyselina 8,11,14-eikosatrienová analogy a deriváty terapeutické užití MeSH
- ledviny metabolismus MeSH
- peptidové fragmenty metabolismus MeSH
- potkani transgenní MeSH
- renin-angiotensin systém účinky léků MeSH
- renin genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We used mass spectrometry to quantitate production of angiotensinogen metabolites in renal artery of 3- and 7-month-old Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR). Tissue fragments were incubated for 15 min in oxygenated buffer, with added angiotensin I. Concentrations of angiotensins I (ANG I), II (ANG II), III (ANG III), IV (ANG IV), angiotensin (1-9) [ANG (1-9)], angiotensin (1-7) [ANG (1-7)], and angiotensin (1-5) [ANG (1-5)], excreted into the buffer during experiment, were measured using liquid chromatography-mass spectrometry (LC/MS) and expressed per mg of dry tissue. Effects of pretreatment with 10 microM perindoprilat on the production of ANG I metabolites were quantitated. Background production of any of ANG I metabolites differed neither between WKY and SHR rats nor between 3- and 7-month-old rats. Perindoprilat pretreatment of renal arteries resulted, as expected, in decrease of ANG II production. However, renal arteries of 7-month-old SHR rats were resistant to ACE inhibitor and did not change ANG II production in response to perindoprilat. In renal arteries, taken from 3-month-old rats, pretreated with perindoprilat, incubation with ANG I, resulted in the level of ANG (1-9) significantly higher in SHR than WKY rats. Our conclusion is that in SHR rats, sensitivity of renal artery ACE to perindoprilat inhibition changes with age.
- MeSH
- angiotensin I metabolismus MeSH
- arteria renalis účinky léků metabolismus MeSH
- hypertenze metabolismus MeSH
- indoly farmakologie MeSH
- peptidové fragmenty metabolismus MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- stárnutí metabolismus MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.
- MeSH
- aktivátory enzymů farmakologie MeSH
- albuminurie komplikace MeSH
- angiotensin I metabolismus MeSH
- angiotensin konvertující enzym metabolismus MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- diminazen analogy a deriváty farmakologie MeSH
- hypertenze maligní komplikace metabolismus patofyziologie moč MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- ledviny účinky léků metabolismus MeSH
- myši MeSH
- peptidové fragmenty metabolismus MeSH
- peptidy farmakologie MeSH
- potkani transgenní MeSH
- regulace genové exprese účinky léků MeSH
- renin-angiotensin systém účinky léků MeSH
- renin genetika MeSH
- sodík moč MeSH
- tělesná hmotnost účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT₁) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. Both TGR and HanSD rats responded to two weeks´ exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT₁receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of suppression of ACE/ANG II/AT₁receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats.
- MeSH
- angiotensin I metabolismus MeSH
- angiotensin II metabolismus MeSH
- angiotensin konvertující enzym metabolismus MeSH
- arteriální tlak MeSH
- hypoxie komplikace enzymologie patofyziologie MeSH
- modely nemocí na zvířatech MeSH
- peptidové fragmenty metabolismus MeSH
- plíce enzymologie MeSH
- plicní hypertenze enzymologie genetika patofyziologie prevence a kontrola MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- protoonkogenní proteiny metabolismus MeSH
- receptor angiotensinu typ 1 metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- renin-angiotensin systém * MeSH
- renin genetika metabolismus MeSH
- signální transdukce MeSH
- vazodilatace MeSH
- vazokonstrikce MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin-angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin-converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.
- MeSH
- angiotensin I metabolismus MeSH
- angiotensin II metabolismus MeSH
- aorta MeSH
- časové faktory MeSH
- epoxid hydrolasy antagonisté a inhibitory chemie MeSH
- hemodynamika účinky léků MeSH
- inhibitory ACE farmakologie terapeutické užití MeSH
- inhibitory enzymů farmakologie terapeutické užití MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- kyseliny mastné mononenasycené metabolismus MeSH
- ledviny účinky léků patofyziologie MeSH
- peptidové fragmenty metabolismus MeSH
- píštěle komplikace MeSH
- potkani transgenní MeSH
- progrese nemoci * MeSH
- renin-angiotensin systém účinky léků MeSH
- renin genetika MeSH
- rozpustnost MeSH
- srdeční frekvence účinky léků MeSH
- srdeční selhání farmakoterapie etiologie patofyziologie MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- vena cava inferior MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- angiotensin I antagonisté a inhibitory chemie metabolismus MeSH
- angiotensin II chemie metabolismus MeSH
- diabetes mellitus 2. typu prevence a kontrola MeSH
- hypertenze farmakoterapie MeSH
- inhibitory ACE aplikace a dávkování metabolismus MeSH
- metabolismus sacharidů MeSH
- přehledová literatura jako téma MeSH
- renin-angiotensin systém účinky léků MeSH
- sacharidy MeSH
- MeSH
- ABO systém krevních skupin MeSH
- angiotensin I metabolismus MeSH
- chronobiologické jevy MeSH
- dospělí MeSH
- fenotyp MeSH
- krevní tlak genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- renin-angiotensin systém genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- angiotensin I farmakologie metabolismus MeSH
- angiotensin II farmakologie metabolismus MeSH
- biologický transport MeSH
- krysa rodu rattus MeSH
- myokard cytologie metabolismus MeSH
- sodíko-draslíková ATPasa genetika metabolismus účinky léků MeSH
- vápník metabolismus MeSH
- vápníkové kanály metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
