Angiotensin-converting Enzyme Inhibitor Captopril Research Articles

Unveiling the potential of angiotensin-converting enzyme as a therapeutic target in head and neck squamous carcinoma

This study investigated the effects of ACE inhibition on Head and Neck Squamous Cell Carcinoma (HNSCC), tumor progression, and the relation of ACE2, AGTR1, ACE, and MAS1 expression with HNSCC patient` survival. ACE inhibitor (Captopril) treatment was applied into Swiss male mice. ACE2, AGTR1, ACE, and MAS1 expression levels were analyzed in HNSCC tumor tissues from The Cancer Genome Atlas (TCGA) database. ACE inhibition reduced cell viability, proliferation, migration, and invasion, increased ROS levels, and induced apoptosis in SCC9 cells. Neoplastic angiogenesis was suppressed by ACE inhibition in the CAM assay. ACE inhibition also reduced the incidence of severe dysplasia/carcinoma in the histological analysis. TCGA data revealed that lower ACE2 levels were associated with poorer survival outcomes, while increased AGTR1 expression correlated with a higher risk of death in HPV-negative patients. ACE upregulation and higher MAS1 expression were observed in HNSCC tumor tissues. ACE inhibition demonstrated anti-cancer effects in HNSCC cells and suppressed neoplastic angiogenesis. It also reduced histological aggressiveness and showed potential predictive value for ACE2 and AGTR1 expression levels in HNSCC. These findings suggest the therapeutic potential of ACE inhibitors in HNSCC treatment, requiring further investigation and validation in clinical settings.

Effects of the angiotensin-converting enzyme inhibitor captopril on occlusal-disharmony-induced cardiac dysfunction in mice

Occlusal disharmony is known to affect not only the oral cavity environment, but also the autonomic nervous system in the heart. Since the renin-angiotensin system (RAS) inhibitor captopril (Cap) is one of the first-line drugs for preventing cardiac remodeling in patients with heart failure, we hypothesized that Cap might prevent cardiac dysfunction induced by occlusal disharmony. Here, to test this idea, we used our bite-opening (BO) mouse model, which was developed by cementing a suitable appliance onto the mandibular incisor. Mice were divided into four groups: (1) Control, (2) BO, (3) Cap, and (4) BO + Cap. After 2 weeks, we evaluated cardiac function by echocardiography and confirmed that cardiac function was significantly decreased in the BO group compared to the control, while Cap ameliorated the dysfunction. Cardiac fibrosis, myocyte apoptosis and oxidative stress-induced myocardial damage in the BO group were significantly increased versus the control, and these increases were suppressed by Cap. Cardiac dysfunction induced by BO was associated with dual phosphorylation on PKCδ (Tyr-311/Thr-505), leading to activation of CaMKII with increased phosphorylation of RyR2 and phospholamban. Our results suggest that the RAS might play an important role in the development of cardiac diseases induced by occlusal anomalies.

ACE2/ACE imbalance mediates bisphenol A-induced lung injury in Wistar rats: Results from captopril versus losartan histo-biochemical study

Bisphenol-A (BPA) is a synthetic chemical compound broadly used in the plastic and epoxy resin industries with a considerable potential for food contamination. Literary reports have suggested that the altered renin-angiotensin system (RAS) is a mechanism for lung injury and inflammation caused by variable agents. The current study sought to investigate the contribution of RAS to BPA-induced lung damage. Moreover, the study assessed whether angiotensin II and/or bradykinin pathways were involved. For this aim, the angiotensin-converting enzyme (ACE) inhibitor captopril (Cap), either alone or combined with bradykinin receptor antagonist icatibant (Icat), was attempted versus the angiotensin receptor blocker losartan (Los). An eight-week study was conducted on forty Wistar male albino rats randomly divided into five equal groups: control, BPA, BPA/Cap, BPA/Los, and BPA/Cap/Icat groups. Captopril (100 mg/mL) and losartan (200 mg/mL) were given orally in drinking water, but icatibant (Icat) was injected subcutaneously (250 μg/kg) during the last two weeks of captopril treatment. Biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung tissues, polymerase chain reaction (PCR) assay for ACE, ACE2, and caspase-3 genes expression, and histological and immunohistochemical studies were carried out to evaluate BPA-mediated pulmonary inflammation/apoptosis. BPA impaired the histological structure of the lungs, increased ACE, ACE2, and caspase-3 expressions at both gene/protein levels, and increased BALF inflammatory cytokines and lung oxidative markers. Inhibiting the ACE activity by captopril maintained the histological lung injury score, restored inflammation and the ACE2/ACE balance, and decreased apoptosis. Further improvement was obtained by the angiotensin II receptor (ATR1) blocker losartan. Icatibant (bradykinin B2 receptor blocker) didn't counteract the observed captopril effects. It was strongly suggested that RAS contributed to BPA-induced lung damage via alteration of ACE2 and ACE expression mediating angiotensin II generation rather than bradykinin.

Snake Venom Components as Therapeutic Drugs in Ischemic Heart Disease.

Ischemic heart disease (IHD), especially myocardial infarction (MI), is a leading cause of death worldwide. Although coronary reperfusion is the most straightforward treatment for limiting the MI size, it has nevertheless been shown to exacerbate ischemic myocardial injury. Therefore, identifying and developing therapeutic strategies to treat IHD is a major medical challenge. Snake venoms contain biologically active proteins and peptides that are of major interest for pharmacological applications in the cardiovascular system (CVS). This has led to their use for the development and design of new drugs, such as the first-in-class angiotensin-converting enzyme inhibitor captopril, developed from a peptide present in Bothrops jararaca snake venom. This review discusses the potential usefulness of snake venom toxins for developing effective treatments against IHD and related diseases such as hypertension and atherosclerosis. It describes their biological effects at the molecular scale, their mechanisms of action according to their different pharmacological properties, as well as their subsequent molecular pathways and therapeutic targets. The molecules reported here have either been approved for human medical use and are currently available on the drug market or are still in the clinical or preclinical developmental stages. The information summarized here may be useful in providing insights into the development of future snake venom-derived drugs.

SARS-CoV-2 induces cardiomyocyte apoptosis and inflammation but can be ameliorated by ACE inhibitor Captopril

Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.

Cardioprotective effect of Ginger in a rat model of myocardial damage and its possible intervention in PERK-ATF4-CHOP-PUMA apoptotic pathway

For today the exact mechanisms of myocardial infarction and ischemia/reperfusion injury are still not fully understood. ER stress and integrated stress response pathways are thought to play an essential role in myocardial damage. This includes activation of endoplasmic reticulum kinase PERK, induction of activating transcription factor ATF4, expression of pro-apoptotic transcription factor CHOP and P53 up-regulated modulator of apoptosis (PUMA) involved in apoptosis control. We used a rat model of isoproterenol-induced myocardial damage to elucidate the possible cardioprotective effect of Ginger through the influence on ER stress-induced apoptotic pathway. We also compared its effect with the ACE inhibitor Captopril. Male albino Wistar rats received 1.0 or 2.0 ml of Zingiber officinale (Ginger) powder suspension (200 mg/ml) daily by intra-gastric intubation for 28 days. Isoproterenol at a dose of 85 mg/kg was IP injected on the 27th and 28th days. Serum aspartate transaminase (AST) level was measured using kinetic kit. Heart tissue was used for RNA extraction, evaluation of gene expression by Q-RT-PCR, immuno-histochemical determination of caspase-3 expression and histopathological studies. Our results showed that Isoproterenol administration increased CHOP-mRNA expression 4 folds in cardiac muscle tissue compared to normal control. Ginger pretreatment significantly decreased both CHOP and ATF4, and PUMA mRNA expression compared to Isoproterenol-treated groups. A significant reduction in ATF4 mRNA expression in a group pretreated with Captopril and Ginger compared to normal control group was observed. The results showed that Ginger reduced AST serum levels which correlated with results of histopathological studies of heart tissue. Our findings suggest that the protective effects of Ginger against myocardium damage induced by Isoproterenol may be mediated by reducing­ the endoplasmic reticulum stress by affecting the ATF4-CHOP-PUMA pathway. Keywords: AST, ATF4, Captopril, CHOP, Ginger, ischemia-reperfusion, Isoproterenol, myocardial damage, PUMA

Angiotensinergic neurotransmission in the bed nucleus of the stria terminalis is involved in cardiovascular responses to acute restraint stress in rats.

The brain angiotensin II acting via AT1 receptors is a prominent mechanism involved in physiological and behavioral responses during aversive situations. The AT2 receptor has also been implicated in stress responses, but its role was less explored. Despite these pieces of evidence, the brain sites related to control of the changes during aversive threats by the brain renin-angiotensin system (RAS) are poorly understood. The bed nucleus of the stria terminalis (BNST) is a limbic structure related to the cardiovascular responses by stress, and components of the RAS system were identified in this forebrain region. Therefore, we investigated the role of angiotensinergic neurotransmission present within the BNST acting via local AT1 and AT2 receptors in cardiovascular responses evoked by an acute session of restraint stress in rats. For this, rats were subjected to bilateral microinjection of either the angiotensin-converting enzyme inhibitor captopril, the selective AT1 receptor antagonist losartan, or the selective AT2 receptor antagonist PD123319 before they underwent the restraint stress session. We observed that BNST treatment with captopril reduced the decrease in tail skin temperature evoked by restraint stress, without affecting the pressor and tachycardic responses. Local AT2 receptor antagonism within the BNST reduced both the tachycardia and the drop in tail skin temperature during restraint. Bilateral microinjection of losartan into the BNST did not affect the restraint-evoked cardiovascular changes. Taken together, these data indicate an involvement of BNST angiotensinergic neurotransmission acting via local AT2 receptors in cardiovascular responses during stressful situations.

Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes.

Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT1 antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. MAP before treatment was 153 ± 2mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.

Control of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals

The free-living, non-parasitic nematode Caenorhabditis elegans is a premier model organism for the study of aging and longevity due to its short lifespan, powerful genetic tools, and conservation of fundamental mechanisms with mammals. Approximately 70 percent of human genes have homologs in C. elegans, including many that encode proteins in pathways that influence aging. Numerous genetic pathways have been identified in C. elegans that affect lifespan, including the dietary restriction pathway, the insulin/insulin-like growth factor (IGF) signaling pathway, and the disruption of components of the mitochondrial electron transport chain. C. elegans is also a powerful system for performing drug screens, and many lifespan-extending compounds have been reported; notably, several FDA-approved medications extend the lifespan in C. elegans, raising the possibility that they can also extend the lifespan in humans. The renin–angiotensin system (RAS) in mammals is an endocrine system that regulates blood pressure and a paracrine system that acts in a wide range of tissues to control physiological processes; it is a popular target for drugs that reduce blood pressure, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Emerging evidence indicates that this system influences aging. In C. elegans, decreasing the activity of the ACE homolog acn-1 or treatment with the ACE-inhibitor Captopril significantly extends the lifespan. In Drosophila, treatment with ACE inhibitors extends the lifespan. In rodents, manipulating the RAS with genetic or pharmacological interventions can extend the lifespan. In humans, polymorphisms in the ACE gene are associated with extreme longevity. These results suggest the RAS plays a conserved role in controlling longevity. Here, we review studies of the RAS and aging, emphasizing the potential of C. elegans as a model for understanding the mechanism of lifespan control.

Angiotensin converting enzyme inhibitor captopril prevents neuronal overexpression of amyloid-beta and alpha-synuclein in Drosophila melanogaster genetic models of neurodegenerative diseases.

Parkinson disease (PD) and Alzheimer's disease (AD) are progressive neurodegenerative disorders characterized by loss of selective neurons in discreet part of the brain. The peptide angiotensin II (Ang II) plays significant role in hippocampal and striatal neurons degeneration through the generation of reactive oxygen species. Blockade of the angiotensin converting enzyme or ATI receptors provides protection in animal models of neurodegenerative diseases. In the present study, the neuroprotective effect of captopril was investigated in Drosophila melanogaster model using the UAS-GAL4 system to express the synuclein and Aβ42 peptide in the flies' neurons. The disease causing human Aβ42 peptide or α-syn was expressed pan-neuronally (elav-GAL4) or dopamine neuron (DDC-GAL4) using the UAS-GAL4 system. Flies were either grown in food media with or without captopril (1, 5, or 10µM). This was followed by fecundity, larva motility, negative geotaxis assay (climbing) and lifespan as a measure of neurodegeneration. Elav-Gal4<Aβ or DDC-GAL4<α-syn flies displayed significant decrease in larva motility when compared with normal control (w1118) which was reversed by the supplementation of the media with captopril (5 or 10 mM) indicative of neuroprotection. Interestingly, supplementation of flies' media with captopril improved climbing activity in Elav-Gal4<Aβ or DDC-GAL4<α-syn flies when compared with vehicle treated only. Moreover, flies grown on captopril caused no significant change in lifespan. Conclusion: Findings from this study confirmed the neuroprotective action of captopril in genetic or familial forms of neurodegeneration.

BLOOD PRESSURE-INDEPENDENT RENOPROTECTION IN DIABETIC RATS TREATED WITH SMALL INTERFERING RNA TARGETING LIVER ANGIOTENSINOGEN

Objective: Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) exerts beneficial effects on blood pressure and kidney function, but its effects in diabetes are still unknown. Design and method: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic with streptozotocin for 18 weeks and treated with vehicle, AGT siRNA, the angiotensin receptor blocker valsartan, the ACE inhibitor captopril, valsartan + siRNA, or valsartan + captopril for the final 3 weeks. Arterial pressure was measured via radiotelemetry. Results: Baseline mean arterial pressure (MAP) was 164 ± 1 mm Hg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a further rise in MAP or a change in glomerular filtration rate. All treatments lowered MAP (by ~50 mm Hg) and cardiac hypertrophy identically. Treatment with siRNA resulted in the largest reduction in AGT, while in combination with valsartan AGT virtually disappeared. Only the dual treatment groups and captopril lowered circulating angiotensin II and aldosterone. No treatment affected renal AGT mRNA expression, confirming the liver-specificity of the siRNA. Yet, siRNA with or without valsartan, and valsartan + captopril, but not valsartan alone, or captopril alone, reduced renal angiotensin I and II. All treatments lowered albuminuria and proteinuria, while only siRNA with or without valsartan improved glomerulosclerosis and podocyte dysfunction. Multiple linear regression confirmed both mean arterial pressure and renal angiotensin II as independent determinants of albuminuria. Conclusions: In conclusion, AGT siRNA exerts renoprotection in diabetic TGR(mREN2)27 rats, and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human diabetic kidney disease.

EFFECT OF CORONAVIRUS INFECTION ON PATIENTS WITH CONTROLLED AND UNCONTROLLED ARTERIAL HYPERTENSION

Objective: To assess the severity of coronavirus infection in patients with hypertension, including resistantand refractory hypertension, and to assess the effect of taking ACE inhibitors and ARBs on the course of COVID-19. Design and method: We called 252 people with an established diagnosis of hypertension, included in the database from November 2018 to July 2021, in order to identify patients who have recently undergone COVID-19. Initially, the patients were divided into groups depending on the number of drugs taken and the achievement of target blood pressure levels. Results: 21 (8.3%) of 252 people had a coronavirus infection. 10 out of 21 patients (48%) noted blood pressure destabilization. 6 (60%) of these 10 initially belonged to the group of uncontrolled hypertension (4 of 6 had refractory hypertension, 2 of 6 had uncontrolled resistant hypertension), however, all of them noted worsening blood pressure control and increased frequency of hypertensive crises compared with the period before COVID-19. In 4 out of 9 patients with initially controlled hypertension, BP was destabilized with subsequent normalization of BP during the recovery period. COVID-19 lasted no more than 14 days in all patients and hypertensive crises was treated by taking short-acting drugs, including an ACE inhibitor (Captopril) and an imidazoline receptor agonist (Moxonidine). 7 (33.3%) and 12 (57.1%) of 21 patients continued to take ACE inhibitors and ARBs, respectively, during coronavirus infection. In 2 (9.6%) of 21 patients, the target BP values were achieved during monotherapy with calcium channel antagonists. All patients with Covid-19 had mild or moderate disease; hospitalization was not required in any of the cases. Conclusions: COVID-19 can destabilize blood pressure in patients with hypertension. Taking an ACE inhibitor / ARB does not worsen the course of coronavirus infection in patients with both controlled and uncontrolled hypertension.

Depletion of the gut microbiota enhances the blood pressure-lowering effect of captopril: implication of the gut microbiota in resistant hypertension.

The role of the gut microbiota in the initiation and progression of hypertension has been newly identified, suggesting that targeting the gut microbiota may provide a new treatment strategy. This entails a complicated interaction between the gut microbiota and different host systems (e.g., immune system) or organs (e.g., gut, spleen) that contribute to blood pressure control. The significance of the gut microbiota in treatment-resistant hypertension is still unknown, owing to a lack of appropriate animal models. Given that the gut microbiota has a variety of enzymatic activities, we hypothesized that the gut microbiota may be involved in the metabolism of antihypertensive medications, causing treatment-resistant hypertension. We investigated this hypothesis in a simple, new hypertension paradigm and found that hypertensive rats pretreated with antibiotics to reduce the gut microbiota had a better response to the angiotensin-converting enzyme inhibitor captopril. This is a simple rodent model for testing the effectiveness of antihypertensive medications. Further mechanistic research may shed light on the pathogenic function of the gut microbiota in resistant hypertension. Our method presents a novel model that has the potential to be employed in the research of resistant hypertension.

Experimental and Molecular Modeling Studies on the Complexation of Chromium(III) with the Angiotensin-Converting Enzyme Inhibitor Captopril.

Captopril (CPT) is an inhibitor of angiotensin I converting enzyme, used as a medication for the treatment of people with high blood pressure, renal insufficiency, and cardiovascular diseases. It inhibits the angiogenesis process, vasoconstriction, and tumor metastasis. Some metal–captopril complexes exhibit antimicrobial activities. In the current work, the formation of the CrIII–CPT complex was studied spectrophotometrically and potentiometrically in aqueous solution. Kinetics of CrIII–CPT complex formation was spectrophotometrically studied over the pH range 3.20–4.20, at an ionic strength of 0.3 M at 30–50 °C. CrIII–CPT complex formation was potentiometrically studied at 25 °C, where ligand protonation constants and complexes’ overall stability constants were calculated. UV–vis absorption spectra were executed to confirm the complex formation. Density functional theory and molecular dynamics simulation were performed to search the geometries of the CrIII–CPT complex. Atoms in molecules and interaction region indicator calculations are used to investigate intermolecular interactions for the formation of CrIII–CPT complex. The antimicrobial activity of the CPT ligand and CrIII–CPT complex on the prevention and control of environmental pathogenic bacteria, as tested on both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli) via agar disc diffusion method, assess the ability to use as an antimicrobial agent. CPT had shown good antimicrobial activity against both types of bacteria, which had increased slightly the zone of inhibition in Cr-CPT that indicates the increased efficacy due to Cr(III) antimicrobial activity via its oxidative damage to the bacterial cell wall. No previous study tested the CPT antimicrobial activity against Gram-positive ones such as S. aureus

Effects of Goldblatt hypertension on rats' hippocampal cholinergic system.

BackgroundThe classical renin-angiotensin system (RAS) has an important role in the cardiovascular system and water homeostasis in the body. Recently, the existence of RAS with all of its components has been shown in the mammalian brain. RAS participates in many brain activities, including memory acquisition and consolidation. Since the cholinergic neurotransmission in the hippocampus is crucial for these functions, this study aims to evaluate the hippocampal angiotensin receptors (ATs) and choline acetyltransferase (ChAT) mRNA in the renovascular hypertensive rats in captopril- and losartan-treated hypertensive rats.MethodsThe rats were randomly divided into four groups of eight animals; sham, Goldblatt two kidney one clip (2K1C) hypertensive rats and Goldblatt 2K1C hypertensive rats received 5 mg/kg captopril and Goldblatt 2K1C hypertensive rats received 10 mg/kg losartan. After 8 days of treatment, the rats were sacrificed and angiotensin-converting enzyme (ACE), ChAT, AT1, and AT2 receptor mRNAs in the hippocampus of rats were assessed by real-time PCR. The Morris water maze test was applied to measure the cognitive functioning of the rats.ResultsHypertensive rats showed impaired acquisition and memory function in the Morris water maze test. Treatment with ACE inhibitor (captopril) and AT1 receptor antagonist (losartan) reversed the observed acquisition and memory deficit in hypertensive rats. Overexpression of AChE, AT1, and AT2 and low expression of ChAT were noted in the hippocampus of rats with Goldblatt hypertension compared with that of the sham group. Treatment with captopril significantly reversed these changes, while treatment with losartan slightly reduced the mentioned effects.ConclusionThe memory-enhancing effect of captopril in renovascular hypertensive rats might lead to increased hippocampal ChAT expression.

Pathophysiology, Treatment and Long-Term Consequences of Heart Failure in Infancy

Introduction: Infants have the highest risk to die from heart failure. However, innovations like beta-blocker treatment introduced more than 50 years ago are not recorded in the guidelines if the clinical trials are missing or be ignored, like propranolol in infants with severe heart failure to congenital heart disease. Methods: We re-analyse our data with propranolol and the ACE-inhibitor captopril in infants with severe heart failure due to congenital heart disease as published 20 years ago and the current long-term follow up data. Results: Propranolol but not Captopril significantly reduces clinical heart failure and neurohormonal activation of the renin angiotensin aldosterone system. Propranolol significantly improve dysautonomia measured by heart rate variability. In contrast to grown up with congenital heart disease – preoperatively treated with digoxin and diuretics - our patients up to the age of 15 years – preoperatively treated with propranolol without frusemide – have normal myocardial function and heart rate variability. Discussion: The evidence-based data of propranolol to treat severe heart failure in infants with congenital heart disease are the best we have. There is no reason to withheld infants from this effective therapy of early life stress due to heart failure. Conclusion: Further studies are needed to proof the impact of propranolol in infants with severe heart failure on long-term neurodevelopment, endothelial- and myocardial function.

Captopril alleviates glucocorticoid-induced osteonecrosis of the femoral head by mediating the ACE2/ Ang-(1-7)/Mas receptor cascade

The renin–angiotensin–aldosterone system (RAAS) is locally expressed in skeletal tissue and is known to affect bone health. This study investigated the therapeutic effects and potential mechanisms of the angiotensin-converting enzyme inhibitor (ACEI) captopril (CAP) in a rat model of glucocorticoid-induced femoral head necrosis (GIONFH). Bone marrow mesenchymal stem cells (mBMSC) from mice treated with dexamethasone (DEX) in vitro and methylprednisolone (MPS)-induced rats in vivo were used to explore the effects and mechanisms of CAP, respectively. Cell proliferation was detected in vitro by the CCK-8 assay, apoptosis by Annexin V-FITC-PI and Western blotting, and reactive oxygen species (ROS) by the DCFH-DA probe. Osteogenic ability was assessed by alkaline phosphatase and alizarin red staining. In vivo hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling, immunohistochemistry, enzyme-linked immunosorbent assay, micro-computed tomography, RT-PCR, and Western blotting were also performed. The in vitro data showed that CAP promotes DEX-induced mBMSC proliferation, reduces apoptosis and ROS accumulation, and promotes osteogenesis. However, these protective effects were partially counteracted by A-779, a specific Mas-receptor antagonist. In vivo experiments showed that CAP prevented MPS-induced osteonecrosis, attenuated inflammation levels, and corrected bone metabolism and bone loss while reversing MPS-induced upregulation of ACE1, AT1-receptor, and RANKL expression and downregulation of ACE2, Mas-receptor, and osteoprotegerin expression. Taken together, these findings demonstrate for the first time that CAP exerts anti-inflammatory, antioxidant, anti-apoptotic, and osteoprotective effects against GIONFH by activating the ACE2/Ang-(1-7)/Mas receptor signaling pathway, which expands a new strategy for the treatment of orthopedic diseases.

Characterising the transcriptome of hypersegmented human neutrophils

Background: Mature human neutrophils are characterised by their multilobed nuclear morphology. Neutrophil hypersegmentation, a pathologic nuclear phenotype, has been described in the alveolar compartment of patients with acute respiratory distress syndrome and in several other contexts. This study aimed to characterise the transcriptional changes associated with neutrophil hypersegmentation. Methods: A model of hypersegmentation was established by exposing healthy peripheral blood neutrophils to the angiotensin converting enzyme inhibitor (ACEi) captopril. Laser capture microdissection (LCM) was then adapted to isolate a population of hypersegmented neutrophils. Transcriptomic analysis of microdissected hypersegmented neutrophils was undertaken using ribonucleic acid (RNA) sequencing. Differential gene expression (DEG) and enrichment pathway analysis were conducted to investigate the mechanisms underlying hypersegmentation. Results: RNA-Seq analysis revealed the transcriptomic signature of hypersegmented neutrophils, with five genes differentially expressed. VCAN, PADI4 and DUSP4 were downregulated, while LTF and PSMC4 were upregulated. Modulated pathways included histone modification, protein-DNA complex assembly and antimicrobial humoral response. The role of PADI4 was further validated using the small molecule inhibitor, Cl-amidine. Conclusions: Hypersegmented neutrophils display a marked transcriptomic signature, characterised by the differential expression of five genes. This study provides insights into the mechanisms underlying neutrophil hypersegmentation and describes a novel method to isolate and sequence neutrophils based on their morphologic subtype.

COVID-19: A New Horizon in Congenital Heart Diseases.

Objective: Previous studies have demonstrated that both children and adult patients with a history of congenital heart disease (CHD) are at high risk for coronavirus disease 2019 (COVID-19) infection. This study investigates the status of COVID-19 infection among children undergoing surgical repair within the past 2 years.Methods: All alive patients operated on in a tertiary referral center between March 2018 and March 2020 were recruited in the present study. Detailed demographics, past medical and surgical history, and physical examination were reviewed for each patient. During the COVID-19 pandemic, data regarding the patient's status were collected by telephone survey from April 15 to April 30, 2020.Results: A total number of 210 patients are analyzed in this study. Participants' median age was 21.59 months [interquartile range (IQR) = 12–54.67], and 125 (59.5%) were female. The median interval between surgery and COVID-19 assessment was 305 days (IQR = 215–400). In addition, 67 (32%) patients used angiotensin receptor blocker (ARB)/angiotensin-converting enzyme (ACE) inhibitor (spironolactone and/or captopril). Sixteen patients (7.6%) were symptomatic and had positive chest CT results and/or RT-PCR compared to the previously reported prevalence of COVID-19 among the pediatric population (2.4% of children with <18 years of age); the prevalence of COVID-19 among the patients operated on due to CHD in the present study was significantly higher (p = 0.00012). Two patients were admitted to the intensive care unit (ICU); one patient was discharged 2 weeks later with acceptable status, and one patient died 2 days after ICU admission due to cardiac and respiratory arrest and myocarditis. The complexity of the underlying cardiac disorders was not different between patients with low risk (p = 0.522), suspicious patients (p = 0.920), and patients positive for COVID-19 (p = 0.234). The ARB/ACE inhibitor consumption was not associated with the COVID-19 infection [p = 0.527, crude odds ratio (OR) = 1.407, 95% CI = 0.489–4.052].Conclusion: Children with a history of previous CHD surgery are more susceptible to infections, especially those infections with pulmonary involvements, as the lung involvement could cause worsening of the patient's condition by aggravating pulmonary hypertension. The results of the current study indicate that these patients are more prone to COVID-19 infection compared to the healthy children population.

Molecular modeling of the interaction of ligands with ACE2-SARS-CoV-2 spike protein complex.

COVID-19 is a new communicable disease with a widespread outbreak that affects all populations worldwide triggering a rush of scientific interest in coronavirus research globally. In silico molecular docking experiment was utilized to determine interactions of available compounds with SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) complex. Chimera and AutoDock Vina were used for protein–ligand interaction structural analysis. Ligands were chosen based on the known characteristics and indications of the drugs as ACE inhibitors (captopril, enalapril, quinapril, moexipril, benazepril, ramipril, perindopril, zofenopril, fosinopril), as ACE2 blockers (losartan, olmesartan), as blood thinning agent (clopidogrel), as cholesterol-lowering prescriptions (simvastatin, atorvastatin), repurposed medications (dexamethasone, hydroxychloroquine, chloroquine), and as investigational drug (remdesivir). Experimental ACE/ACE2 inhibitors are also included: Sigma ACEI, N-(2-aminoethyl)-1-aziridine-ethanamine (NAAE), nicotianamine (NAM), and MLN-4760 (ACE2 inhibitor). The best docked conformations were all located in the ACE2 protein, 50% docked at the interface with lower scores and only clopidogrel and hydroxychloroquine docked at the spike protein. Captopril, moexipril, benazepril, fosinopril, losartan, remdesivir, Sigma ACEI, NAA, and NAM interacted and docked at the interface of ACE2 and SARS-CoV-2 spike protein complex. This may have significant implication in enhancing our understanding of the mechanism to hinder viral entry into the host organism during infection.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40203-021-00114-w.