ACE Levels Research Articles

ACE and chitotriosidase as possible predictive biomarkers for activity of sarcoidosis in correlation with PET/CT findings

Sarcoidosis is a granulomatous disease which can afflict virtually any tissue in human body, most commonly the mediastinal lymph nodes and lungs. Pathohistological confirmation is the gold standard in establishing a diagnosis; however, determining the activity of the disease requires multiple clinical, radiographic and laboratory procedures. PET/CT scan is considered the gold standard for determining the presence of active granuloma, but has several significant limitations (radioactive material, cost, overall access to device). ACE and chitotriosidase are biomarkers used for diagnosis of sarcoidosis, and could have a place in determining the activity of the disease, when compared with the results of PET/CT scan. We have compared the levels of ACE and chitotriosidase with the levels of SUVmax values in patients with sarcoidosis. SUVmax and chitotriosidase level were significantly correlated both at the baseline and after the follow-up period, regardless of gender, age, duration of disease and radiography stage, while SUVmax and ACE level were not. Chitotriosidase had also shown a significant predictive ability of the decrease of the activity of sarcoidosis represented as the decrease of SUVmax as the effect of therapy in comparison with ACE. In the absence of ideal biomarker for sarcoidosis (high sensitivity, specificity and stability), chitotriosidase can be used in determining the activity of disease, as it had shown a significant correlation to the gold standard- PET/CT scan.

Non-fermented and fermented milk intake in relation to risk of ischemic heart disease and to circulating cardiometabolic proteins in swedish women and men: Two prospective longitudinal cohort studies with 100,775 participants

BackgroundThe effect of milk on the risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) is unclear. We aimed to examine the association between non-fermented and fermented milk consumption on these endpoints and investigate the relationship between milk intake and cardiometabolic-related proteins in plasma.MethodsOur study is based on two Swedish prospective cohort studies that included 59,998 women and 40,777 men without IHD or cancer at baseline who provided repeated measures of diet and lifestyle factors and plasma proteomics data in two subcohorts. Through registry linkage, 17,896 cases with IHD were documented during up to 33 years of follow-up, including 10,714 with MI. We used time-updated multivariable Cox regression analysis to examine non-fermented or fermented milk intake with time to IHD or MI. Using high-throughput multiplex immunoassays, 276 cardiometabolic plasma proteins were measured in two subcohorts. We applied multivariable-adjusted regression models using a discovery-replication design to examine protein associations with increasing consumption of non-fermented or fermented milk.ResultsThe results for non-fermented milk differed by sex (p-value for interaction = 0.01). In women, we found a pattern of successively greater risk of IHD and MI at non-fermented milk intake levels higher than 1.5 glasses/day. Compared with an intake of 0.5 glass/day (100 mL/day), non-fermented milk intake of 2 glasses/day in women conferred a multivariable-adjusted hazard ratio (HR) of 1.05 (95% CI 1.01–1.08) for IHD, an intake of 3 glasses/day an HR of 1.12 (95% CI 1.06–1.19), and an intake of 4 glasses/day an HR of 1.21 (95% CI 1.10–1.32). Findings were similar for whole, medium-fat, and low-fat milk. We did not detect higher risks of IHD with increasing milk intakes in men. Fermented milk intake was unrelated to the risk of IHD or MI in either sex. Increasing non-fermented milk intake in women was robustly associated with a higher concentration of plasma ACE2 and a lower concentration of FGF21.ConclusionsWe show a positive association between high amounts of non-fermented milk intake and IHD in women but not men. We suggest metabolic pathways related to ACE2 and FGF21 potentially underlie the association.Graphical abstractOur analysis of two large cohort studies involving 100,775 participants and 17,896 clinically confirmed IHD events supports a dose–response positive association between non-fermented milk intake higher than 300 mL/day with higher rates of IHD (and acute MI specifically) in women, but not in men. The higher risk of IHD with high milk intake in women was evident, irrespective of the fat content of the milk. Fermented milk intake was unrelated to the risk of IHD in both women and men. Non-fermented milk intake was associated in different directions with circulating levels of ACE2 and FGF21 in women—two essential cardiometabolic proteins, also related to IHD in women in our study.

Circulating ACE2 and the association of endothelial progenitor cell in CAD patients

Abstract Background/Introduction Angiotensin-converting enzyme (ACE) 2 is the homologue of ACE, and the local up-regulation of ACE2 expression associates to antiatherosclerosis. ACE2 hydrolyzes the angiogensin II, which related to impair of endothelial progenitor cell (EPC) function. EPCs maintain the integrity of vascular endothelium in case of damage. Decreased number of EPCs associate thrombosis. Purpose To investigate the circulating ACE2 and the link to EPC in CAD patients. Methods Data from 650 patients with stable angina pectoris requiring invasive coronary angiography were enrolled. They were divided into two groups according to the median value of ACE2. Two interventional cardiologists diagnosed obstructive CAD by angiography review. Demographic characteristics and clinical outcomes were compared between groups. Results In all subjects (median age 67 years, male=66.9%), a higher ACE2 level indicates elder, higher prevalence of hypertension, diabetes mellitus and chronic kidney disease. Significant EPC elevation when CAD numbers increased in higher ACE2 group (SVD vs. DVD vs. MVD = 0.005 vs. 0.006 vs. 0.007, p value=0.044). In multivariate analysis, higher ACE2 is positively correlated to triple vessel disease (TVD vs. no CAD, adjusted odds ratio=1.627, 95% CI 1.026-2.579). Conclusions Our data demonstrated higher circulation ACE2 links to EPCs in CAD patients.

Effects of Angiotensin-I-Converting Enzyme (ACE) Mutations Associated with Alzheimer's Disease on Blood ACE Phenotype.

Our recent analysis of 1200+ existing missense ACE mutations revealed that 400+ mutations are damaging and led us to hypothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer's disease (AD). Here, we quantified blood ACE levels in EDTA plasma from 41 subjects with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C, and G325R are truly damaging and likely transport-deficient, with the ACE levels in plasma at only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and likely did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has the potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in our cell model of the transport-deficient ACE mutation Q1069R.

Predictors of COVID-19 severity among a cohort of Egyptian patients

BackgroundAs the outbreak of COVID-19 progresses, prognostic markers for the identification of high-risk individuals are urgently needed. The angiotensin system is implicated in the pathogenesis of COVID-19 as ACE2 is the cellular receptor for SARS-COV-2 virus, and expression of the ACE2 gene could regulate an individual’s susceptibility to infection. In addition, the balance between ACE and ACE2 activity may play a role in the severity of COVID-19.Aim of workThe aim of the work is to explore the role of ACE1 I/D and ACE2 G8790A gene variants and serum ACE l/ACE2 ratio as risk factors for severity of COVID-19 infection.MethodsOne hundred and eighty COVID-19 patients were divided into three groups: mild (60 patients), moderate (60 patients), and severe (60 patients). The enzyme levels of ACE and ACE2 were measured by ELISA. ACE I/D (rs4646994) was assayed using PCR and ACE2 (rs2285666) gene variant was determined using real-time PCR.ResultsACE/ACE2 ratio was significantly lower in the mild group than in the moderate-to-severe group (P < 0.001). GG (reference) genotype and G allele of ACE2 were more frequent in mild group, AA (variant) genotype, and A allele were more frequent in severe group (P value < 0.001). In the multiple logistic regression, COVID-19 severity was associated with older age (> 50y) (OR 10.4, 95% CI 3.8–28.4, P < 0.001), comorbidities (OR 8.2, 95% CI 1.6–42.1, P 0.012), and higher ACE/ACE2 ratio (OR 8.3, 95% CI 3.7–18.6 P < 0.001) were independent significant predictors of severity. Haplotype analysis revealed that patients with D allele of the ACE gene combined with the A allele of the ACE2 gene had nearly double the risk of having severe COVID infection (OR = 1.9, 95% CI 1.1–3.5, P = 0.024).ConclusionOld age (> 50 years), presence of comorbidities, and a high ACE/ACE2 ratio are recognized as pivotal predictors of COVID-19 severity.

Association of Angiotensin Converting Enzyme Phenotypes and Polymorphisms with Clinical Outcomes in SARS-CoV2 Patients with Hypertension in an Urban Emergency Department.

The role of Angiotensin-converting enzyme (ACE and ACE2) phenotypes and polymorphisms in modulating severe acute respiratory syndrome coronavirus (SARS-- CoV2) infection in hypertensive patients remains unclear. Our objective was to determine the distribution of ACE and ACE2 receptor phenotypes by patient demographics and correlate ACE and ACE2 levels of activity with SARS-CoV-2 outcomes. Hypertensive patients treated for SARS-CoV-2 at an urban emergency department (ED) were prospectively enrolled in a cohort study between August 2020 and April 2021. Blood samples were collected during ED visits or hospitalization. Outcome measures including hospitalization, intensive care unit (ICU) admission, and 30-day mortality were obtained from electronic health records. Multivariable logistic regression was used. Of the 150 patients enrolled, 60% were Black, 32% Hispanic/Latinx, 4% Non-Hispanic Whites, and 4% others. The mean age was 59 (+/-14) years. The rate of hospitalization was high (86%) and Hispanic/Latinx had a higher likelihood of ICU admission. Patients harboring the rs2285666 genotype TT, AA, and GC alleles were more likely to be admitted to ICU, and those with TT and AA had higher mortality. The ACE level was a significant predictor of hospitalization with a protective effect in both unadjusted and adjusted results. Hispanics/Latinx had a four times higher likelihood of ICU admission compared to all others, and age was significantly associated with 30-day mortality. Our results show that even after adjusting for age, race, and sex, ACE levels remained a predictor of hospitalization. ACE/ACE2 phenotypes and genotypes potentially play an important role in disease progression in SARS-CoV-2 patients.

ACE2 and TMPRSS2 in human kidney tissue and urine extracellular vesicles with age, sex, and COVID-19.

SARS-CoV-2 virus infects cells by engaging with ACE2 requiring protease TMPRSS2. ACE2 is highly expressed in kidneys. Predictors for severe disease are high age and male sex. We hypothesized that ACE2 and TMPRSS2 proteins are more abundant (1) in males and with increasing age in kidney and (2) in urine and extracellular vesicles (EVs) from male patients with COVID-19 and (3) SARS-CoV-2 is present in urine and EVs during infection. Kidney cortex samples from patients subjected to cancer nephrectomy (male/female; < 50years/˃75years, n = 24; ˃80years, n = 15) were analyzed for ACE2 and TMPRSS2 protein levels. Urine from patients hospitalized with SARS-CoV-2 infection was analyzed for ACE2 and TMPRSS2. uEVs were used for immunoblotting and SARS-CoV-2 mRNA and antigen detection. Tissue ACE2 and TMPRSS2 protein levels did not change with age. ACE2 was not more abundant in male kidneys in any age group. ACE2 protein was associated with proximal tubule apical membranes in cortex. TMPRSS2 was observed predominantly in the medulla. ACE2 was elevated significantly in uEVs and urine from patients with COVID-19 with no sex difference compared with urine from controls w/wo albuminuria. TMPRSS2 was elevated in uEVs from males compared to female. ACE2 and TMPRSS2 did not co-localize in uEVs/apical membranes. SARS-CoV-2 nucleoprotein and mRNA were not detected in urine. Higher kidney ACE2 protein abundance is unlikely to explain higher susceptibility to SARS-CoV-2 infection in males. Kidney tubular cells appear not highly susceptible to SARS-CoV-2 infection. Loss of ACE2 into urine in COVID could impact susceptibility and angiotensin metabolism.

Association between Adverse Childhood Experiences and Internalizing Symptoms in Adults at a Wellness Centre in India

Abstract Background: Adverse childhood experiences (ACE or childhood trauma) include very stressful and potentially traumatic events linked to a higher risk of mental health challenges and chronic conditions. India has an opportunity to study the association between ACE exposure and internalizing symptoms (depression and anxiety). To evaluate the association between exposure to ACE and internalizing symptoms (depression and anxiety) at a wellness centre in India. Methods and Material: This cross-sectional study studied a convenience sample of 909 individuals who self-assessed ACE exposure, depression (Major Depression Inventory: MDI), and anxiety levels (Generalized Anxiety Disorder: GAD-7). Logistic regression models evaluated the association between ACE and depression and anxiety levels. Results: The results show a strong association between ACE levels and depression as well as anxiety. Individuals with medium (1-3 ACEs), high (4-6 ACEs), and very high (&gt; =7 ACEs) exposure to childhood trauma are at 2–7 odds of having major depression and 1–3 odds of having anxiety. Moreover, both Gen Z and Gen Y are at a higher risk of depression and anxiety compared with Gen X. Conclusions: The research extends the findings from global research on ACE and mental health (depression, anxiety) in India, highlighting the strong association. Future work should expand the samples across the geography to enhance the insights.

12268 Hypercalcemia Alert: Exploring The Link To Isolated Bone Marrow Sarcoidosis

Abstract Disclosure: M. Renzu: None. C.M. Hubers: None. V. mehta: None. A. Qazi: None. D.K. Yerasuri: None. Introduction: Sarcoidosis, a complex disorder marked by granuloma formation in diverse organs, often affects the lungs, but can involve various systems as well. Rare cases of bone marrow involvement may mimic conditions like multiple myeloma, emphasizing the need to consider sarcoidosis in patients with bone marrow abnormalities, especially those without typical myeloma features. Case Presentation: A 79-year-old white male with a medical history of hypertension, hyperlipidemia, deep venous thrombosis, prostate cancer in remission, chronic knee pain, and basal cell carcinoma presented for pre-operative evaluation, as he was scheduled for an elective orthopedic procedure. On routine lab work, he was found to have acute hypercalcemia and normocytic anemia. This finding raised suspicion for an underlying systemic pathology. He reported that he did not take any calcium or vitamin D supplements at home. Subsequent endocrine assessment, including evaluation of parathyroid hormone and vitamin D levels, revealed a non-PTH-mediated hypercalcemia. The persistence of hypercalcemia prompted further investigations, including assessments for multiple myeloma by oncology. The workup was negative for multiple myeloma but significant for granulomas on bone marrow biopsy, a finding consistent with sarcoidosis. Additionally, angiotensin converting enzyme levels were elevated at the time of diagnosis. Interventions led to the resolution of hypercalcemia following steroid therapy of prednisone 20 mg daily and close follow up with endocrinology. As part of his follow up, ACE levels are being regularly monitored, with the patient going for lab work every other month. Discussion: Bone marrow biopsies rarely reveal granulomas and sarcoidosis accounts for only a very small percentage of these findings. The standard workup for sarcoidosis typically does not include bone marrow biopsies. By integrating biopsies into the standard diagnostic protocol researchers may gain insights into the etiology and mechanisms driving this manifestation of sarcoidosis, ultimately improving diagnostic accuracy and patient care. Distinguishing sarcoidosis from multiple myeloma also poses diagnostic challenges, necessitating thorough evaluation in patients with bone marrow abnormalities. Despite its rarity, clinical suspicion for sarcoidosis should be considered in patients with underlying hematologic disorders or malignancies. Additionally, sarcoidosis exhibits geographical variation, being less common in Japanese men and more prevalent in African American women. This highlights the importance of considering demographic factors when evaluating patients for sarcoidosis and its extrapulmonary manifestations. Long-term outcomes in isolated bone marrow sarcoidosis remain unclear, warranting surveillance for progression to multiple myeloma or other lymphoproliferative disorders. Presentation: 6/2/2024

8301 A Rare Case of IgG4-Related Hypophysitis

Abstract Disclosure: P. Kesavan Chary: None. J.M. Silverstein: None. Background: IgG4-related disease (IgG4-RD) is an immune-mediated condition that presents as systemic inflammation and fibrosis of tissues, often affecting multiple organs. Isolated IgG4-related Hypophysitis is rare and characterized by lymphoplasmacytic infiltration of the pituitary gland by IgG4-positive plasma cells. A combination of clinical, serologic, radiologic, and histopathologic findings is used for diagnosis of IgG4-RD and approximately two-thirds of all patients have elevated serum IgG4 levels. We report a case of isolated IgG4-related Hypophysitis in a middle-aged woman serologically negative for IgG4-related disease. Case Report: A 52 year old female with history of steroid dependent severe persistent asthma, allergic rhinitis, and chronic sinusitis presented with one month of headache, polyuria, and polydipsia. MRI Brain demonstrated an enlarged, rounded pituitary gland 16 x 11 x 9 mm, with homogeneous enhancement, extension into the suprasellar cistern, and mild thickening of the infundibulum suspected to represent a pituitary adenoma. Lab evaluation revealed mild hyperprolactinemia (prolactin 83.2, normal 4.8-23.3 ng/mL) and secondary adrenal insufficiency based on an abnormal high-dose cosyntropin stimulation test in the setting of a low adrenocorticotrophic hormone (ACTH) level (&amp;lt;2.0 pg/mL). Remaining pituitary hormone levels were normal. Inpatient work-up for polyuria and polydipsia showed a low urine specific gravity of 1.003. An overnight water deprivation test was performed. Baseline urine osmolality (UOsm) was 95 mOsm/kg and serum sodium was 144 mmol/L; after 3 hours of water deprivation, serum Osm increased to 301 mOsm/kg (275-300 mOsm/kg) and UOsm only to 215 mOsm/kg, while her sodium increased to 145 mmol/L. Results were felt to be consistent with AVP deficiency (Central Diabetes Insipidus) and the patient was started on desmopressin. Because of the presence of AVP deficiency, further work-up was done to evaluate for an infiltrative process or malignancy. ANA, RPR, ESR, CRP, CBC, ACE level, T-SPOT, and IgG subclasses were unremarkable. Further imaging studies yielded a negative nuclear bone scan and PET/CT scan. For diagnostic purposes, the patient underwent biopsy via an endoscopic endonasal transsphenoidal approach. Pathology showed the presence of &amp;gt;10 IgG4+ plasma cells in a single high-power field, consistent with a diagnosis of IgG4-related Hypophysitis. Conclusion: Isolated IgG4-related Hypophysitis is the least common clinical presentation of IgG4-RD, which is itself a rare and relatively newly recognized condition. IgG4-related Hypophysitis should be suspected in patients presenting with AVP deficiency and pituitary stalk enlargement with an otherwise negative work up. Presentation: 6/2/2024

Macular Star and Neuroretinitis with Optic Disk Edema

Neuroretinitis is an inflammatory disorder of the eye presenting with unilateral visual loss, optic disc edema, and subsequent formation of a macular star. Neuroretinitis can be classified as idiopathic, infectious and recurrent. Following a detailed patient history, essential work-up should include Bartonella antibody titers, the rapid plasma reagin (RPR) test, the tuberculin skin test, ACE and lysozyme levels, and a two-view chest X-ray. Among infectious etiologies of neuroretinitis, cat scratch disease caused by Bartonella henselae is the most frequently observed, accounting for two-thirds of cases. Recurrent neuroretinitis is characterized by poorer visual recovery and visual field loss. Patients should be informed about the possibility of recurrence to prevent severe vision loss.

The Strong Effect of Propolis in Suppressing NF-κB, CysC, and ACE2 on a High-fat Diet

Background: A high fat diet (HFD)is one of the main causes of obesity and is closely linked to metabolic disorders brought on by stress and malfunctioning tissues. Propolis (Trigona Honey) is considered to be helpful in treating inflammatory diseases because it has also been demonstrated to have anti-inflammatory and anti-free radical properties. This study to demonstrate how much propolis supplementation affects BW, NF-κB, CysC, and ACE2 levels in Wistar rats (Rattus norvegicus) fed a HFD. Methods: Post-test and control group designs in an experimental setup. A total of twenty-four rats were randomly assigned to four groups of six. Group I received a normal diet for sixteen weeks (ND), Group II received a high fat diet (HFD) for sixteen weeks (HFD), Group III received an HFD for sixteen weeks plus propolis for eight weeks (HFD-8), and Group IV received an HFD and propolis for sixteen weeks (HFD-16). Using the Enzyme-Linked Immunosorbent Assay (ELISA), body weight (BW), serum NF-κB, Cys C, and ACE2 levels were measured before treatment (week 0), after 8 weeks of HFD (HFD-8) (week 8), and after 16 weeks of HFD (HFD-16). Results: The mean starting weight in the ND, HFD, HFD-8, and HFD-16 groups did not differ significantly (p &gt; 0.001). By week eight, the HFD group's body weight had increased considerably (254.83 grams vs. 202.0 grams) in comparison to the ND group (p&lt;0.001). The HFD and HFD-8 groups' body weight increased significantly at week 16 in comparison to the ND group (334.83 grams and 269.50 grams vs. 208.67 grams) (p&lt;0.001). At week 16, there was no discernible difference in mean BW between ND and HFD-16 (p &gt; 0.001). There was no significant difference found in the mean initial NF-κB levels between the ND, HFD, HFD-8, and HFD-16 groups (p &gt; 0.001). At week 8, NF-κB levels in the HFD group were significantly higher (5,038 ng/ml vs. 3,655 ng/ml) (p&lt;0.001) than in the ND group. At week 16, NF-κB levels in the HFD and HFD-8 groups were notably higher than those in the ND group (p&lt;0.001), at 6,136 ng/ml and 4,378 ng/ml, respectively, compared to 3,775 ng/ml. Between ND and HFD-16, there was no significant distinction in the mean NF-κB levels at week 16 (p&gt;0.001). There was no significant difference observed in the mean CysC and ACE2 between the ND, HFD, HFD-8, and HFD-16 groups (p &gt; 0.001). CysC and ACE2 levels in the HFD group were significantly higher than those in the ND group at week 8, and in the HFD and HFD-8 groups, they were significantly higher than those in the ND group at week 16. When propolis is administered for eight weeks, the rise in BW, NF-κB, CysC, and ACE2 is suppressed until the eighth week, at which point it increases once more until the sixteenth week. Propolis administration, however, will halt the rise in BW, NF-κB, CysC, and ACE2 until the sixteenth week. Conclusion: Propolis administration for 16 weeks can suppress the increase in BW, LI, RI, NF-κB, CysC and ACE2 levels in rats given a high fat diet (HFD).

Expression levels of ACE and ACE2 in the placenta and white adipose tissue of lean and obese pregnant women

Background This study evaluated the expression of ACE and ACE2 in the placenta and white adipose tissue in lean and obese women, and correlated their levels with anthropometric, clinical, and laboratory parameters, and tissue count of inflammatory cells. Methods A cross-sectional analytical study was performed with 49 pregnant women and their respective newborns. Samples of placenta and adipose tissue were used for measuring mRNA expression for ACE and ACE2 through qRT-PCR. Inflammatory cell counting was performed through conventional microscopy. Results An increase in ACE expression and a decrease in ACE2 were observed in the placenta and adipose tissue of women with obesity. ACE2 levels showed a negative correlation with pre-pregnancy BMI and total cholesterol. Conclusion Maternal obesity can modulate the expression of RAS components in the placenta and white adipose tissue, with ACE2 correlated with pre-pregnancy BMI and total cholesterol.

A hypothesis linking the renin-angiotensin, kallikrein-kinin systems, and disseminated coagulation in COVID-19

In this article we present a hypothesis based on the relationship between four physiological systems: the renin-angiotensin system (RAS), the kallikrein-kinin system (KKS), the arachidonic acid (AA) cascade, and platelet aggregation/coagulation − in the context of COVID-19. The central point of our proposition relies on ACE2 levels, which reduce following SARS-CoV-2 entry in the cell. The following cascade of events. Triggered by this reduction, involves the increase in Ang II levels and its consequent binding to AT1-R, initiating the release of pro-inflammatory cytokines such as TNF-α, IL-1, IL-10, and IL-12. These pro-inflammatory cytokines activate immune cells, including mast cells, which release heparin, thus activating Coagulation factor XII and increasing pre-kallikrein (PK) production. Consequently, there is an increase in bradykinin (BK) levels. BK, via its receptor BKB2-R, induces Ca2 + release increasing secreted phospholipase A2 (sPLA2) levels. Concomitantly, both the imbalance in Ang II/AT1-R and BK/BKB2-R signaling contribute to sPLA2 activation, inducing the release of arachidonic acid (AA) from cell membrane phospholipids, by cyclooxygenase-2 (COX-2) cleavage to produce prostaglandin G2 (PGG2), and later prostaglandin H2 (PGH2). At least, PGH2 is converted to thromboxane A2 (TXA2), which is involved in the platelet aggregation process. Platelet aggregation further increases TXA2 levels, initiating a positive feedback loop leading to further platelet activation and clot formation. Ultimately, this cascade of events may contribute to the development of a pre-thrombotic state and increase the risk of mortality, in COVID-19. We believe that this integrated approach could provide a deeper understanding of the underlying mechanisms of COVID-19 and guide future therapeutic strategies.

ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch

BackgroundThoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in β-aminopropionitrile fumarate (BAPN)-induced TAD.MethodsA mouse model of TAD induced by BAPN and IL-1β -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis.ResultsWe found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression.ConclusionACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models.

Host factors that define the cellular tropism of SARS-CoV-2 beyond the cognate ACE2 receptor are poorly defined. Here we report that SARS-CoV-2 replication is restricted at a post-entry step in a number of ACE2-positive airway-derived cell lines due to tonic activation of the cGAS-STING pathway mediated by mitochondrial DNA leakage and naturally occurring cGAS and STING variants. Genetic and pharmacological inhibition of the cGAS-STING and type I/III IFN pathways as well as ACE2 overexpression overcome these blocks. SARS-CoV-2 replication in STING knockout cell lines and primary airway cultures induces ISG expression but only in uninfected bystander cells, demonstrating efficient antagonism of the type I/III IFN-pathway in productively infected cells. Pharmacological inhibition of STING in primary airway cells enhances SARS-CoV-2 replication and reduces virus-induced innate immune activation. Together, our study highlights that tonic activation of the cGAS-STING and IFN pathways can impact SARS-CoV-2 cellular tropism in a manner dependent on ACE2 expression levels.

Exploring the Th2 Response in Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Potential Modulator of the Renin-Angiotensin System (RAS) Pathway in Hypertension Development.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is alarmingly increasing alongside the cases of obesity worldwide. MASLD is an underestimated metabolic abnormality closely linked with a higher risk of developing systemic arterial hypertension (SAH). However, the underlying mechanism of association between MASLD and SAH remains unknown. Inflammation may link these two entities by regulating the renin-angiotensin system (RAS). For this reason, in this study, we evaluated the hepatic expression of a cytokine profile and critical molecules in the RAS pathway in patients with morbid obesity and MASLD, both with SAH. We found a statistically significant correlation between ACE levels and the cytokines IL-4, IL-10, and IL-13 of Th2 response. Furthermore, according to a multiple linear regression analysis, the cytokines IL-4 and IL-13 were the best predictors of ACE levels. Moreover, we observed increased hepatic IL-13 expression in patients with morbid obesity, MASLD, and SAH compared to those without SAH. These results allow us to propose, for the first time, that the Th2 response, through regulating the RAS, could play a critical role in developing SAH in individuals with MASLD and obesity.

Correlation between Exposure to UFP and ACE/ACE2 Pathway: Looking for Possible Involvement in COVID-19 Pandemic.

The overlap between the geographic distribution of COVID-19 outbreaks and pollution levels confirmed a correlation between exposure to atmospheric particulate matter (PM) and the SARS-CoV-2 pandemic. The RAS system is essential in the pathogenesis of inflammatory diseases caused by pollution: the ACE/AngII/AT1 axis activates a pro-inflammatory pathway, which is counteracted by the ACE2/Ang(1-7)/MAS axis, which activates an anti-inflammatory and protective pathway. However, ACE2 is also known to act as a receptor through which SARS-CoV-2 enters host cells to replicate. Furthermore, in vivo systems have demonstrated that exposure to PM increases ACE2 expression. In this study, the effects of acute and sub-acute exposure to ultrafine particles (UFP), originating from different anthropogenic sources (DEP and BB), on the levels of ACE2, ACE, COX-2, HO-1, and iNOS in the lungs and other organs implicated in the pathogenesis of COVID-19 were analyzed in the in vivo BALB/c male mice model. Exposure to UFP alters the levels of ACE2 and/or ACE in all examined organs, and exposure to sub-acute DEP also results in the release of s-ACE2. Furthermore, as evidenced in this and our previous works, COX-2, HO-1, and iNOS levels also demonstrated organ-specific alterations. These proteins play a pivotal role in the UFP-induced inflammatory and oxidative stress responses, and their dysregulation is linked to the development of severe symptoms in individuals infected with SARS-CoV-2, suggesting a heightened vulnerability or a more severe clinical course of the disease. UFP and SARS-CoV-2 share common pathways; therefore, in a "risk stratification" concept, daily exposure to air pollution may significantly increase the likelihood of developing a severe form of COVID-19, explaining, at least in part, the greater lethality of the virus observed in highly polluted areas.

Could Ocular Glands Be Infected by SARS-CoV-2?

The aim of the study was to investigate the expression levels of ACE2 in ocular glands and to investigate the effect of S protein on them. Male C57BL/6J mice were used for the experiments. The expression levels of ACE2 are highest in the Meibomian glands, followed by the conjunctiva, the cornea, and the lacrimal glands. Co-immunoprecipitation assays confirmed direct binding between ACE2 and S protein in ocular surface epithelia and Meibomian glands. CD45+ cell infiltration was found in the S protein treatment group, which was accompanied by upregulation of inflammation-related cytokines. There was also prominent cell apoptosis in the S protein treatment group. In conclusion, not only the cornea and the conjunctiva, but also the Meibomian glands express ACE2, and S protein could induce ocular surface epithelial cell and Meibomian gland cell inflammation and apoptosis.

The study of single nucleotide polymorphism in a promoter region of ACE-2 receptor gene in the samples of Iraqi population with COVID-19.

Angiotensin-converting enzyme 2 (ACE2) is an essential receptor on the host cell's cell membrane. It's interesting to note that the entry point receptor ACE2 protein and the severe acute respiratory syndrome (SARS) coronavirus are correlated. This study aimed to determine the influence of the ACE gene genotype and explore the effects of genetic variation in the promotor region of the ACE-2 gene receptor in SARS COV-2 patients. The 225 participants were categorized into two groups (75 infected and 150 control) according to the results of Real Time -polymerase chain reaction (RT-PCR), IgM, and IgG, also included two types of samples were collected for diagnosis hematological and molecular study. The hematological and biochemical parameters showed significant differences between the two studied groups according to D. dimer, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), white blood cells (WBC), lymphocyte, packed cell volume (PCV) (P˂0.0001), also red blood cell (RBC) (P = 0.0034). While the results of hemoglobin (HB) and platelet displayed non-significant differences between the two groups (p value 0.6811 and 0.9201 respectively). In addition, the sequencing result in the promotor of the ACE-2 gene detected novel eight polymorphisms and recorded them in NCBI under no. (ON959139). The ACE D/D polymorphism associated with increased levels of ACE could represent a genetic risk factor in addition the discovery stems from the prospect that genetic differences could lead to differing responses to COVID-19 therapies.