Evidence for treatment with estradiol for women with SARS-CoV-2 infection.

BACKGROUND: Given that an individual's age and gender are strongly predictive of coronavirus disease 2019 (COVID-19) outcomes, do such factors imply anything about preferable therapeutic options? METHODS: An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in 5-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and peri-/post-menopausal (> 50 years). RESULTS: The incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is higher in women than men (by about + 15%) and, in contrast, the fatality rate is higher in men (about + 50%). Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a significantly higher risk of infection than men in the same 5-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in peri- and postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years, there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17ß-estradiol influences expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which plays a role in SARS-CoV-2 cellular entry, propensity score matching was performed for the women's sub-cohort, comparing users vs. non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women > 50 years receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95% CI [0.18, 0.62] and the hazard ratio (HR) was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 years), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. CONCLUSIONS: As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.

ACE2, the kidney and the emergence of COVID-19 two decades after ACE2 discovery.

Angiotensin-converting enzyme II (ACE2) is a homologue of angiotensin-converting enzyme discovered in 2000. From the initial discovery, it was recognized that the kidneys were organs very rich on ACE2. Subsequent studies demonstrated the precise localization of ACE2 within the kidney and the importance of this enzyme in the metabolism of Angiotensin II and the formation of Angiotensin 1-7. With the recognition early in 2020 of ACE2 being the main receptor of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the interest in this protein has dramatically increased. In this review, we will focus on kidney ACE2; its localization, its alterations in hypertension, diabetes, the effect of ACE inhibitors and angiotensin type 1 receptor blockers (ARBs) on ACE2 and the potential use of ACE2 recombinant proteins therapeutically for kidney disease. We also describe the emerging kidney manifestations of COVID-19, namely the frequent development of acute kidney injury. The possibility that binding of SARS-CoV-2 to kidney ACE2 plays a role in the kidney manifestations is also briefly discussed.

Design of an engineered ACE2 as a novel therapeutics against COVID-19.

The interaction between the angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of the spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a pivotal role in virus entry into the host cells. Since recombinant ACE2 protein has been suggested as an anti-SARS-CoV-2 therapeutic agent, this study was conducted to design an ACE2 protein with more desirable properties. In this regard, the amino acids with central roles in enzymatic activity of the ACE2 were substituted. Moreover, saturation mutagenesis at the interaction interface between the ACE2 and RBD was performed to increase their interaction affinity. The best mutations to increase the structural and thermal stability of the ACE2 were also selected based on B factors and mutation effects. The obtained resulted revealed that the Arg273Gln and Thr445Gly mutation have drastically reduced the binding affinity of the angiotensin-II into the active site of ACE2. The Thr27Arg mutation was determined to be the most potent mutation to increase the binding affinity. The Asp427Arg mutation was done to decrease the flexibility of the region with high B factor. The Pro451Met mutation along with the Gly448Trp mutation was predicted to increase the thermodynamic stability and thermostability of the ACE2. The designed therapeutic ACE2 would have no enzymatic activity while it could bear stronger interaction with Spike glycoprotein of the SARS-CoV-2. Moreover, decreased in vivo enzymatic degradation would be anticipated due to increased thermostability. This engineered ACE2 could be exploited as a novel therapeutic agent against COVID-19 after necessary evaluations.

The Controversy of Renin-Angiotensin-System Blocker Facilitation Versus Countering COVID-19 Infection.

The ongoing COVID-19 pandemic has produced serious turmoil world-wide. Lung injury causing acute respiratory distress syndrome seems to be a most dreaded complication occurring in ∼30%. Older patients with cardiovascular comorbidities and acute respiratory distress syndrome have an increased mortality. Although the precise mechanisms involved in the development of lung injury have not been fully elucidated, the role of the extended renin-angiotensin system seems to be pivotal. In this context, angiotensin-converting enzyme 2 (ACE2), an angiotensin-converting enzyme homologue, has been recognized as a facilitator of viral entry into the host, albeit its involvement in other counter-regulatory effects, such as converting angiotensin (Ang) II into Ang 1-7 with its known protective actions. Thus, concern was raised that the use of renin-angiotensin system inhibitors by increasing ACE2 expression may enhance patient susceptibility to the COVID-19 virus. However, current data have appeased such concerns because there has been no clinical evidence of a harmful effect of these agents as based on observational studies. However, properly designed future studies will be needed to further confirm or refute current evidence. Furthermore, other pathways may also play important roles in COVID-19 transmission and pathogenesis; spike (S) protein proteases facilitate viral transmission by cleaving S protein that promotes viral entry into the host; neprilysin (NEP), a neutral endopeptidase known to cleave natriuretic peptides, degrades Ang I into Ang 1-7; NEP can also catabolize bradykinin and thus mitigate bradykinin's role in inflammation, whereas, in the same context, specific bradykinin inhibitors may also negate bradykinin's harmful effects. Based on these intricate mechanisms, various preventive and therapeutic strategies may be devised, such as upregulating ACE2 and/or using recombinant ACE2, and exploiting the NEP, bradykinin and serine protease pathways, in addition to anti-inflammatory and antiviral therapies. These issues are herein reviewed, available studies are tabulated and pathogenetic mechanisms are pictorially illustrated.

Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB.

PURPOSE OF REVIEW: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the aggressive coronavirus disease (COVID-19) pandemic. Recently, investigators have stipulated that COVID-19 patients receiving angiotensin-converting-enzyme inhibitors (ACEI) may be subject to poorer outcomes. This editorial presents the available evidence to guide treatment practices during this pandemic. RECENT FINDINGS: Recent studies from Wuhan cohorts provide valuable information about COVID-19. A cohort with 52 critically ill patients revealed cardiac injury in 12% of patients. Worse outcomes appear to be more prevalent in patients with hypertension and diabetes mellitus (DM), possibly due to overexpression of angiotensin-converting enzyme 2 (ACE2) receptor in airway alveolar epithelial cells. Investigators suspect that SARS-CoV-2 uses the ACE2 receptor to enter the lungs in a mechanism similar to SARS-CoV. Several hypotheses have been proposed to date regarding the net effect of ACEI/ARB on COVID-19 infections. Positive effects include ACE2 receptor blockade, disabling viral entry into the heart and lungs, and an overall decrease in inflammation secondary to ACEI/ARB. Negative effects include a possible retrograde feedback mechanism, by which ACE2 receptors are upregulated. Even though physiological models of SARS-CoV infection show a theoretical benefit of ACEI/ARB, these findings cannot be extrapolated to SARS-CoV-2 causing COVID-19. Major cardiology scientific associations, including ACC, HFSA, AHA, and ESC Hypertension Council, have rejected these correlation hypotheses. After an extensive literature review, we conclude that there is no significant evidence to support an association for now, but given the rapid evolvement of this pandemic, findings may change.

Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation.

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that potently degrades angiotensin II to angiotensin 1-7. Previous studies showed that injection of the enzymatic ectodomain of recombinant ACE2 (rACE2) markedly increases circulatory levels of ACE2 activity, and effectively lowered blood pressure in angiotensin II-induced hypertension. However, due to the short plasma half-life of rACE2, its therapeutic potential for chronic use is limited. To circumvent this, we generated a chimeric fusion of rACE2 and the immunoglobulin fragment Fc segment to increase its plasma stability. This rACE2-Fc fusion protein retained full peptidase activity and exhibited greatly extended plasma half-life in mice, from less than two hours of the original rACE2, to over a week. A single 2.5 mg/kg injection of rACE2-Fc increased the overall angiotensin II-conversion activities in blood by up to 100-fold and enhanced blood pressure recovery from acute angiotensin II induced hypertension seven days after administration. To assess rACE2-Fc given weekly on cardiac protection, we performed studies in mice continuously infused with angiotensin II for 28 days and in a Renin transgenic mouse model of hypertension. The angiotensin II infused mice achieved sustained blood pressure control and reduced cardiac hypertrophy and fibrosis. In chronic hypertensive transgenic mice, weekly injections of rACE2-Fc effectively lowered plasma angiotensin II and blood pressure. Additionally, rACE2-Fc ameliorated albuminuria, and reduced kidney and cardiac fibrosis. Thus, our chimeric fusion strategy for rACE2-Fc is suitable for future development of new renin angiotensin system-based inhibition therapies.

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.

BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. RESULTS: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. CONCLUSIONS: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Angiotensin-Converting Enzyme 2 Attenuates Bleomycin-Induced Lung Fibrosis in Mice.

BACKGROUND: Local renin-angiotensin system (RAS) activation has been shown to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). It has been reported that angiotensin-converting enzyme 2 (ACE2) could inhibit RAS-mediated epithelial injury and fibrogenesis and that ACE2 deficiency could aggravate acute and chronic lung injury. Through research, it could be deduced that ACE2 could protect against pulmonary fibrosis as a therapeutic target. METHODS: Time-course analysis of the pathological characteristics of bleomycin-induced lung fibrosis was undertaken in a mouse model, and the effect of exogenous ACE2 on lung fibrosis was studied. Immunohistchemistry (IHC) staining and western blot (WB) testing for AGT and ACE2 were performed to evaluate the regulation of local RAS. TUNEL staining was used to observe epithelial apoptosis. Leukocyte common antigen (LCA) and pulmonary surfactant-associated protein A (SP-A) IHC staining and WB testing were performed to assess the inflammatory response and epithelial regeneration. Masson's staining and a hydroxyproline assay were performed to examine collagen deposition. IHC staining and WB testing for TGF-ß1 and α-SMA were performed to investigate the regulation of pro-fibrotic cytokines and the activation of fibroblasts. RESULTS: Exogenous ACE2 attenuated bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of AGT. ACE2 decreased the apoptosis index and LCA levels and ameliorated the dynamic change in SP-A level, thus protecting against epithelial injury. Reductions of TGF-ß1 and α-SMA were also found in ACE2-treated mice, indicating the inhibition of fibrogenesis. CONCLUSION: ACE2 attenuated bleomycin-induced lung fibrosis as an anti-inflammatory anti-apoptotic and anti-fibrotic agent, and it might be a promising therapeutic target for IPF.

Effective treatment of hypertension by recombinant Lactobacillus plantarum expressing angiotensin converting enzyme inhibitory peptide.

BACKGROUND: Hypertension is considered the most serious risk factor for cardiovascular disease. Angiotensin-converting enzyme inhibitory peptides (ACEIPs), which are made from tuna frame protein (TFP) and yellow fin sole frame protein (YFP), have been used previously to treat hypertension. However, the production of these short peptides is usually dependent on enzymatic hydrolysis, resulting in a digested mixture that makes it difficult to purify the ACEIPs. Although it has been reported that ACEIPs could be produced in recombinant Escherichia coli strains, the use of lactic acid bacteria in the production of ACEIPs has not been demonstrated. RESULTS: In this study, the ACEIP coding sequences from TFP and YFP were joined through an arginine linker and expressed in the Lactobacillus plantarum (Lb. plantarum) NC8 strain by an inducible vector pSIP-409. Then, the antihypertensive effects were determined in the model of spontaneously hypertensive rats (SHRs) by measuring the blood pressure, hematology, blood biochemistry and nitric oxide (NO), endothelin (ET) and angiotensin II (Ang II) levels. The results showed that oral administration of recombinant Lb. plantarum NC8 (RLP) significantly decreased systolic blood pressure (P < 0.01) during treatment, which lasted for at least 10 days after the last dose. Furthermore, the presence of RLP resulted in an increased level of NO, as well as decreased levels of ET and Ang II in plasma, heart, and kidney. In addition, a dramatically decreased triglyceride level was also observed even though there was no significant change in hematology or blood biochemistry. Although some drawbacks were still observed, such as the presence of an antibiotic selection marker, no obvious side effects or bacterial translocation were observed in vivo, indicating the potential application of RLP in the treatment of hypertension. CONCLUSION: These results demonstrated the effectiveness and safety of RLP on the treatment of hypertension.

MSCs with ACE II gene affect apoptosis pathway of acute lung injury induced by bleomycin.

PURPOSE: The aim of this study was to evaluate the effect and related mechanisms of Mesenchymal stem cells (MSCs) and Angiotensin converting enzyme II (ACE II) on acute lung injury (ALI). METHODS: MSCs were separated from umbilical cord cells, and the changes of phenotype before and after ACE II silence were observed using Flow Cytometer. ALI model was induced by 10 mg/mL bleomycin in 60 Balb/c mice, and the rest 8 mice were regarded as the baseline group. The mice were randomly divided into four groups (n = 15): control, ACE II, stem, and stem + ACE II. The apoptotic index (AI) was calculated using TUNEL, and the detection of protein and mRNA of Bax, Bak and p53, Bcl-2, Grp78, CHOP and Caspase 12 were used by western-blot and RT-PCR, respectively. RESULTS: The umbilical cord cells differentiated into stable MSCs about 14 days, and ACE II transfection reached a peak at the 5th day after transfection. ACE II silence did not affect the phenotype of MSCs. All the proteins and mRNAs expression except Bcl-2 in the stem and stem + ACE II were significantly lower than those in control from 8 h (p < 0.05, p < 0.01), while Bcl-2 exhibited an opposite trend. Stem + ACE II performed a better effect than single stem in most indexes, including AI (p < 0.05, p < 0.01). CONCLUSIONS: The co-administration of MSCs and ACE II can significantly suppress apoptosis in ALI mice, and may be an effective clinical treatment for ALI.

Combination therapy with human umbilical cord mesenchymal stem cells and angiotensin-converting enzyme 2 is superior for the treatment of acute lung ischemia-reperfusion injury in rats.

Acute lung ischemia-reperfusion injury (ALIRI) is a serious disease that seriously affects human's life. In this study, we aimed to explore a more effective treatment method by combining human umbilical cord mesenchymal stem cells (HUMSCs) and angiotensin-converting enzyme 2 (ACE2) for ALIRI. Fifty rats were firstly divided into five groups, namely sham surgery group (sham) and four model groups (model, ACE2, HUMSCs and HUMSCs + ACE2) that were reperfused with 0.1 ml physiological saline (PS), 0.1 ml PS containing 1 × 10(6) lentiviral-ACE2/HUMSCs/ACE2 + UMSCs, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and western blot assays were then conducted to detect the messenger RNA (mRNA) and protein levels of inflammatory cytokines [intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), tumour necrosis factor α (TNF-α), nuclear factor κB (NF-κB), platelet-derived growth factor (PDGF) and angiotensin II (Ang II)], antioxidant proteins [NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1)], DNA damage and apoptotic indicators [BCL2-associated X (Bax), cleaved caspase-3 (C-Csp 3), cleaved-poly(ADP-ribose) polymerase (C-PARP), Y-H2AX], anti-apoptotic indicator (Bcl-2) and smooth muscle cell proliferation indicator [connexin 43 (Cx43)]. According to the qRT-PCR and western results, the mRNA and protein expression levels of ICAM-1, VCAM-1, TNF-α, NF-κB, PDGF, Bax, C-Csp 3, C-PARP and Y-H2AX were significantly higher in model group than those in sham group and they were significantly reduced by HUMSCs or ACE2 treatment (P < 0.05). On the contrary, Bcl-2 showed an opposite expression trend with the previous proteins. The mRNA and protein levels of NQO1 and HO-1 were sequentially increased in sham, model, ACE2, HUMSCs and HUMSCs + ACE2 groups. Besides, HUMSCs combined with ACE2 exhibited a better inhibition effect on ALIRI than HUMSCs or ACE2 alone (P < 0.05). In summary, HUMSCs combined with ACE2 was demonstrated to have the best therapeutic effect on ALIRI through anti-inflammation, oxidative stress and anti-apoptotic processes.

Targeting angiotensin-converting enzyme 2 as a new therapeutic target for cardiovascular diseases.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes several vasoactive peptides, including angiotensin II (Ang-II; a vasoconstrictive/proliferative peptide), which it converts to Ang-(1-7). Ang-(1-7) acts through the Mas receptor to mediate vasodilatory/antiproliferative actions. The renin-angiotensin system involving the ACE-Ang-II-Ang-II type-1 receptor (AT1R) axis is antagonized by the ACE2-Ang-(1-7)-Mas receptor axis. Loss of ACE2 enhances adverse remodeling and susceptibility to pressure and volume overload. Human recombinant ACE2 may act to suppress myocardial hypertrophy, fibrosis, inflammation, and diastolic dysfunction in heart failure patients. The ACE2-Ang-(1-7)-Mas axis may present a new therapeutic target for the treatment of heart failure patients. This review is mainly focused on the analysis of ACE2, including its influence and potentially positive effects, as well as the potential use of human recombinant ACE2 as a novel therapy for the treatment cardiovascular diseases, such as hypertension and heart failure.

Targeting the Renin-Angiotensin System (RAS) for Neuropsychiatric Disorders.

BACKGROUND: Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS: We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION: The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.

Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension.

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was to evaluate cytoskeletal defects in BMPR2-associated PAH. Expression arrays on our Bmpr2 mutant mouse lungs revealed cytoskeletal defects as a prominent molecular consequence of universal expression of a Bmpr2 mutation (Rosa26-Bmpr2(R899X)). Pulmonary microvascular endothelial cells cultured from these mice have histological and functional cytoskeletal defects. Stable transfection of different BMPR2 mutations into pulmonary microvascular endothelial cells revealed that cytoskeletal defects are common to multiple BMPR2 mutations and are associated with activation of the Rho GTPase, Rac1. Rac1 defects are corrected in cell culture and in vivo through administration of exogenous recombinant human angiotensin-converting enzyme 2 (rhACE2). rhACE2 reverses 77% of gene expression changes in Rosa26-Bmpr2(R899X) transgenic mice, in particular, correcting defects in cytoskeletal function. Administration of rhACE2 to Rosa26-Bmpr2(R899X) mice with established PAH normalizes pulmonary pressures. Together, these findings suggest that cytoskeletal function is central to the development of BMPR2-associated PAH and that intervention against cytoskeletal defects may reverse established disease.

Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin II with high efficiency leading to the formation of angiotensin-(1-7). ACE2 within the kidneys is largely localized in tubular epithelial cells and in glomerular epithelial cells. Decreased glomerular expression of this enzyme coupled with increased expression of ACE has been described in diabetic kidney disease, both in mice and humans with type 2 diabetes. Moreover, both ACE2 genetic ablation and pharmacological ACE2 inhibition have been shown to increase albuminuria and promote glomerular injury. Studies using recombinant ACE2 have shown the ability of ACE2 to rapidly metabolize Ang II in vivo and form the basis for future studies to examine the potential of ACE2 amplification in the therapy of diabetic kidney disease and cardiovascular disease.

Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia.

OBJECTIVE: Alveolar hypoxia as a result of high altitude leads to increased pulmonary arterial pressure. The renin-angiotensin system is involved in the regulation of pulmonary arterial pressure through angiotensin-converting enzyme 2 (ACE2). It remains unknown whether ACE2 administration alters pulmonary vascular pressure in hypoxia. METHODS: We investigated 12 anesthetized pigs instrumented with arterial, central venous, and Swan-Ganz catheters exposed to normobaric hypoxia (fraction of inspired oxygen = 0.125) for 180 minutes. After taking baseline measurements in normoxia and hypoxia, ACE2 400 µg·kg(-1) was administered to 6 animals, and another 6 served as control. Ventilatory variables, arterial blood gases, ventilation/perfusion (V̇A/Q̇) relationships, and plasma angiotensin II concentrations were assessed before and at 30, 90, and 150 minutes in hypoxia after ACE2 or placebo administration. Hemodynamic variables and cardiac output were observed every 30 minutes. RESULTS: We observed lower pulmonary arterial pressure (maximum: 30 vs 39 mm Hg, P < .01) and lower pulmonary vascular resistance (maximum: 4.1 vs 7.5 Wood units, P <.01) in animals treated with ACE2. There was a trend (P =.09) toward lower angiotensin II plasma concentrations among ACE2-treated animals. Cardiac variables and systemic arterial pressure in hypoxia remained unaffected by ACE2. Ventilation/perfusion relationships and Pao(2) did not differ between groups. CONCLUSIONS: In acute pulmonary hypertension, administration of ACE2 blunts the rise in pulmonary arterial pressure that occurs in response to hypoxia. Recombinant ACE2 may be a treatment option for high altitude pulmonary edema and hypoxia-associated pulmonary hypertension.

Angiotensin converting enzyme (ACE) inhibitors as radiation countermeasures for long-duration space flights.

Angiotensin converting enzyme (ACE) inhibitors are effective countermeasures to chronic radiation injuries in rodent models, and there is evidence for similar effects in humans. In rodent models ACE inhibitors are effective mitigators of radiation injury to kidney, lung, central nervous system (CNS) and skin, even when started weeks after irradiation. In humans, the best data for their efficacy as radiation countermeasures comes from retrospective studies of injuries in radiotherapy patients. We propose that ACE inhibitors, at doses approved for human use for other indications, could be used to reduce the risk of chronic radiation injuries from deep-space exploration. Because of the potential interaction of ACE inhibitors and microgravity (due to effects of ACE inhibitors on fluid balance) use might be restricted to post-exposure when/if radiation exposures reached a danger level. A major unresolved issue for this approach is the sparse evidence for the efficacy of ACE inhibitors after low-dose-rate exposure and/or for high-LET radiations (as would occur on long-duration space flights). A second issue is that the lack of a clear mechanism of action of the ACE inhibitors as mitigators makes obtaining an appropriate label under the Food and Drug Administration Animal Rule difficult.

Clathriolide from marine demosponge Clathria (Thalysias) vulpina (Lamarck, 1814): previously undescribed macrocylic lactone with attenuating potential against angiotensin converting enzyme.

Angiotensin-I converting enzyme catalyses the rate-determined step of the conversion of angiotensin-I to angiotensin-II that narrows the blood vessels, and angiotensin-I converting enzyme inhibitors were recognised as important medications for hypertension-related diseases. Chemical investigation of angiotensin-I converting enzyme inhibitors from marine demospongiae Clathria (Thalysias) vulpina (family Microcionidae), resulted in a previously undescribed 22-membered macrocyclic lactone derivative, named as clathriolide. The studied compound showed potential angiotensin converting enzyme attenuation property (IC50 0.41 mM), which was comparable with the standard captopril (IC50 0.36 mM). Clathriolide revealed significantly greater antioxidant potentials against free radical species (IC50 < 1 mM) in comparison with the standard α-tocopherol (IC50 > 1.5 mM). Superior electronic characteristics (topological polar surface area > 100) coupled with relatively smaller binding energy and docking score of clathriolide with the aminoacyl residues of angiotensin-I converting enzyme (-11.5 and -12.2 kcal/mol, respectively) described its potential inhibitory property against angiotensin-I converting enzyme.

Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells.

PURPOSE: Radiation-induced lung injury is a major dose-limiting toxicity for thoracic radiation therapy patients. In experimental models, treatment with angiotensin converting enzyme (ACE) inhibitors mitigates radiation pneumonitis; however, the mechanism of action is not well understood. Here, we evaluate the direct role of ACE inhibition on lung immune cells. METHODS AND MATERIALS: ACE expression and activity were determined in the lung immune cell compartment of irradiated adult rats after either high dose fractionated radiation therapy to the right lung (5 fractions × 9 Gy) or a single dose of 13.5 Gy partial body irradiation. Mitigation of radiation-induced pneumonitis with the ACE-inhibitor lisinopril was evaluated in the 13.5 Gy rat partial body irradiation model. During pneumonitis, we characterized inflammation and immune cell content in the lungs and bronchoalveolar lavage fluid. In vitro mechanistic studies were performed using primary human monocytes and the human monocytic THP-1 cell line. RESULTS: In both the partial body irradiation and fractionated radiation therapy models, radiation increased ACE activity in lung immune cells. Treatment with lisinopril improved survival during radiation pneumonitis (P = .0004). Lisinopril abrogated radiation-induced increases in bronchoalveolar lavage fluid monocyte chemoattractant protein 1 (chemokine ligand 2) and MIP-1a cytokine levels (P < .0001). Treatment with lisinopril reduced both ACE expression (P = .006) and frequency of CD45+ CD11b+ lung myeloid cells (P = .004). In vitro, radiation injury acutely increased ACE activity (P = .045) and reactive oxygen species (ROS) generation (P = .004) in human monocytes, whereas treatment with lisinopril blocked radiation-induced increases in both ACE and ROS. Radiation-induced ROS generation was blocked by pharmacologic inhibition of either NADPH oxidase 2 (P = .012) or the type 1 angiotensin receptor (P = .013). CONCLUSIONS: These data demonstrate radiation-induced ACE activation within the immune compartment promotes the pathogenesis of radiation pneumonitis, while ACE inhibition suppresses activation of proinflammatory immune cell subsets. Mechanistically, our in vitro data demonstrate radiation directly activates the ACE/type 1 angiotensin receptor pathway in immune cells and promotes generation of ROS via NADPH oxidase 2.