Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure

Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted

Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges

Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 1–7 and the apelin/APJ are two important peptide systems which exert diverse effects on the cardiovascular system. ACE2 is a key negative regulator of the renin-angiotensin system (RAS) where it metabolizes angiotensin (Ang) II into Ang 1–7, an endogenous antagonist of Ang II. Both the prolonged activation of RAS and the loss of ACE2 can be detrimental as they lead to functional deterioration of the heart and progression of cardiac, renal, and vascular diseases. Recombinant human ACE2 in an animal model of ACE2 knockout mice lowers Ang II. These interactions neutralize the pressor and subpressor pathologic effects of Ang II by producing Ang 1–7 levels in vivo, that might be cardiovascular protective. ACE2 hydrolyzes apelin to Ang II and, therefore, is responsible for the degradation of both peptides. Apelin has emerged as a promising peptide biomarker of heart failure. The serum level of apelin in cardiovascular diseases tends to be decreased. Apelin is recognized as an imperative controller of systemic blood pressure and myocardium contractility. Dysregulation of the apelin/APJ system may be involved in the predisposition to cardiovascular diseases, and enhancing apelin action may have important therapeutic effects

ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance

Antagonism of angiotensin 1-7 prevents the therapeutic effects of recombinant human ACE2

Activation of the angiotensin 1-7/Mas receptor (MasR) axis counteracts angiotensin II (Ang II)-mediated cardiovascular disease. Recombinant human angiotensin-converting enzyme 2 (rhACE2) generates Ang 1-7 from Ang II. We hypothesized that the therapeutic effects of rhACE2 are dependent on Ang 1-7 action. Wild type male C57BL/6 mice (10-12 weeks old) were infused with Ang II (1.5 mg/kg/d) and treated with rhACE2 (2 mg/kg/d). The Ang 1-7 antagonist, A779 (200 ng/kg/min), was administered to a parallel group of mice. rhACE2 prevented Ang II-induced hypertrophy and diastolic dysfunction while A779 prevented these beneficial effects and precipitated systolic dysfunction. rhACE2 effectively antagonized Ang II-mediated myocardial fibrosis which was dependent on the action of Ang 1-7. Myocardial oxidative stress and matrix metalloproteinase 2 activity was further increased by Ang 1-7 inhibition even in the presence of rhACE2. Activation of Akt and endothelial nitric oxide synthase (eNOS) by rhACE2 were suppressed by the antagonism of Ang 1-7 while the activation of pathological signaling pathways was maintained. Blocking Ang 1-7 action prevents the therapeutic effects of rhACE2 in the setting of elevated Ang II culminating in systolic dysfunction. These results highlight a key cardioprotective role of Ang 1-7, and increased Ang 1-7 action represents a potential therapeutic strategy for cardiovascular diseases. KEY MESSAGES: Activation of the renin-angiotensin system (RAS) plays a key pathogenic role in cardiovascular disease. ACE2, a monocarboxypeptidase, negatively regulates pathological effects of Ang II. Antagonizing Ang 1-7 prevents the therapeutic effects of recombinant human ACE2. Our results highlight a key protective role of Ang 1-7 in cardiovascular disease

Impact of district mental health care plans on symptom severity and functioning of patients with priority mental health conditions: the Programme for Improving Mental Health Care (PRIME) cohort protocol

Background: The Programme for Improving Mental Health Care (PRIME) sought to implement mental health care plans (MHCP) for four priority mental disorders (depression, alcohol use disorder, psychosis and epilepsy) into routine primary care in five low- and middle-income country districts. The impact of the MHCPs on disability was evaluated through establishment of priority disorder treatment cohorts. This paper describes the methodology of these PRIME cohorts. Methods: One cohort for each disorder was recruited across some or all five districts: Sodo (Ethiopia), Sehore (India) , Chitwan (Nepal), Dr. Kenneth Kaunda (South Africa) and Kamuli (Uganda), comprising 17 treatment cohorts in total (N = 2182). Participants were adults residing in the districts who were eligible to receive mental health treatment according to primary health care staff, trained by PRIME facilitators as per the district MHCP. Patients who screened positive for depression or AUD and who were not given a diagnosis by their clinicians (N = 709) were also recruited into comparison cohorts in Ethiopia, India, Nepal and South Africa. Caregivers of patients with epilepsy or psychosis were also recruited (N = 953), together with or on behalf of the person with a mental disorder, depending on the district. The target sample size was 200 (depression and AUD), or 150 (psychosis and epilepsy) patients initiating treatment in each recruiting district. Data collection activities were conducted by PRIME research teams. Participants completed follow-up assessments after 3 months (AUD and depression) or 6 months (psychosis and epilepsy), and after 12 months. Primary outcomes were impaired functioning, using the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS), and symptom severity, assessed using the Patient Health Questionnaire (depression), the Alcohol Use Disorder Identification Test (AUD), and number of seizures (epilepsy). Discussion: Cohort recruitment was a function of the clinical detection rate by primary health care staff, and did not meet all planned targets. The cross-country methodology reflected the pragmatic nature of the PRIME cohorts: while the heterogeneity in methods of recruitment was a consequence of differences in health systems and MHCPs, the use of the WHODAS as primary outcome measure will allow for comparison of functioning recovery across sites and disorders

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Стереотипи вживання тютюну, поінформованість курців та витрати на тютюнові вироби: результати опитування у місті Сурат, Індія

BACKGROUND: As smoking is a major risk factor in India, the objective of present study was to assess smoking patterns, expenditure and awareness amongst smokers and to examine factors associated with the severity of smoking in Surat city. METHODS: Community-based cross-sectional study was conducted with the use of pre-structured questionnaire tool targeting 281 current smokers in the slums of 20 Urban Health Centers. Smokers were categorized based on pack-years, which means the number of packs smoked per day multiplied by the duration of smoking (mild <5, moderate 5-15, and severe >15), and based on the number of cigarette/bidis smoked per day without the duration component (mild <10, moderate 10-19, and severe ≥20). Factors associated with severity of smoking were examined within two approaches with help of Epi-info mediated analysis. RESULTS: Lower severity of smoking was associated with smaller number of family members who smoke (p<0.001). Groups of mild and moderate-severe smokers were similar with regards to education, socioeconomic class, and awareness regarding hazards of smoking (p>0.05). With the influence of friends (50%), about 60% smokers engage into this habit before the age of 20 years. Though only 20% of current smokers were not aware of the consequences of active smoking, more than 50% did not know about the same for passive smoking. The lowest socioeconomic class spends 44% of their income on tobacco products compared to 7% in the highest class. CONCLUSION: The study provides insights for information, education and counseling (IEC) activities which should take into account health impact of bidi smoking, low awareness of health impact of passive smoking, and higher percentage of total monthly expenditure on tobacco among low-income household resulting in crowding out of expenditures on other needs.АКТУАЛЬНОСТЬ: Поскольку курение является важным фактором риска в Индии, целью данного исследования была оценка стереотипов потребления табака, расходов на табак и знаний о влиянии на здоровье, а также факторов, связанных с тяжестью курения, среди курильщиков города Сурат. МЕТОДЫ: Одномоментный опрос 281 курильщика с использованием структурированной анкеты был проведен на базе населенного пункта в трущобах, окружающих 20 городских центров здоровья. Курильщиков классифицировали в зависимости от показателя пачко-лет, то есть количества пачек, выкуриваемых в день, умноженных на количество лет курения (легкие – менее 5 пачко-лет, умеренные – 5-15 пачко-лет, тяжелые – более 15), и в зависимости от количества сигарет, выкуриваемых в день, без учета длительности курения (легкие – менее 10 сигарет в день, умеренные – 10-19 сигарет в день, тяжелые – 20 и более сигарет в день). Факторы тяжести курения, измеренной с помощью двух подходов, анализировали с использованием программы Epi-info. РЕЗУЛЬТАТЫ: Меньшая тяжесть курения сочеталась с меньшим количеством курящих членов семьи (p<0.001). Группы курильщиков различной тяжести не различались по образованию, социально-экономическому статусу, уровню знаний об опасности курения. Под влиянием друзей (50%) около 60% курильщиков вовлекаются в курение до 20 лет. Хотя только 20% не знали о последствиях активного курения, более 50% не знали о влиянии пассивного курения. Представители низшего социального класса затрачивают на курение 44% своих доходов по сравнению с 7% доходов представителей высшего класса. ЗАКЛЮЧЕНИЕ: Исследование дает информацию для просветительских действий, которые должны принимать во внимание влияние на здоровье курения биди, низкую осведомленность о влиянии на здоровье пассивного курения, а также более высокую долю расходов на табак в бюджете малоимущих курильщиков, что ведет к вытеснению расходов на другие важные потребности. КЛЮЧЕВЫЕ СЛОВА: табачный дым, осведомленность, расходы, биди, Индия.АКТУАЛЬНОСТЬ: Поскольку курение является важным фактором риска в Индии, целью данного исследования была оценка стереотипов потребления табака, расходов на табак и знаний о влиянии на здоровье, а также факторов, связанных с тяжестью курения, среди курильщиков города Сурат. МЕТОДЫ: Одномоментный опрос 281 курильщика с использованием структурированной анкеты был проведен на базе населенного пункта в трущобах, окружающих 20 городских центров здоровья. Курильщиков классифицировали в зависимости от показателя пачко-лет, то есть количества пачек, выкуриваемых в день, умноженных на количество лет курения (легкие – менее 5 пачко-лет, умеренные – 5-15 пачко-лет, тяжелые – более 15), и в зависимости от количества сигарет, выкуриваемых в день, без учета длительности курения (легкие – менее 10 сигарет в день, умеренные – 10-19 сигарет в день, тяжелые – 20 и более сигарет в день). Факторы тяжести курения, измеренной с помощью двух подходов, анализировали с использованием программы Epi-info. РЕЗУЛЬТАТЫ: Меньшая тяжесть курения сочеталась с меньшим количеством курящих членов семьи (p<0.001). Группы курильщиков различной тяжести не различались по образованию, социально-экономическому статусу, уровню знаний об опасности курения. Под влиянием друзей (50%) около 60% курильщиков вовлекаются в курение до 20 лет. Хотя только 20% не знали о последствиях активного курения, более 50% не знали о влиянии пассивного курения. Представители низшего социального класса затрачивают на курение 44% своих доходов по сравнению с 7% доходов представителей высшего класса. ЗАКЛЮЧЕНИЕ: Исследование дает информацию для просветительских действий, которые должны принимать во внимание влияние на здоровье курения биди, низкую осведомленность о влиянии на здоровье пассивного курения, а также более высокую долю расходов на табак в бюджете малоимущих курильщиков, что ведет к вытеснению расходов на другие важные потребности. КЛЮЧЕВЫЕ СЛОВА: табачный дым, осведомленность, расходы, биди, Индия