Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19.
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ABSTRACT:
SUBMITTER: Oudit GY
PROVIDER: S-EPMC7224688 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19.
Oudit Gavin Y GY Pfeffer Marc A MA
European heart journal 20200501 19
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Project description:The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance, which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene, which is involved in the regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow the completion of their viral replication cycles. Furthermore, a dataset using a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs, which negatively correlated with the expression of genes that code for sterol response element-binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Moreover, ACE2 expression in human subcutaneous adipose tissue can be regulated through changes in diet. Validation of the in silico data revealed a higher expression of ACE2, TMPRSS2 and SREBP1 in vitro in lung epithelial cells from obese subjects compared to non-obese subjects. To our knowledge this is the first study to show upregulation of ACE2 and TMPRSS2 in obesity. In silico and in vitro results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.
| S-EPMC7531362 | biostudies-literature
Project description:ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.
| S-EPMC10681288 | biostudies-literature
Project description:The coronavirus disease (COVID-19) pandemic is a global health priority. Given that cardiovascular diseases (CVD) are the leading cause of morbidity around the world and that several trials have reported severe cardiovascular damage in patients infected with SARS-CoV-2, a substantial number of COVID-19 patients with underlying cardiovascular diseases need to continue their medications in order to improve myocardial contractility and to prevent the onset of major adverse cardiovascular events (MACEs), including heart failure. Some of the current life-saving medications may actually simultaneously expose patients to a higher risk of severe COVID-19. Angiotensin-converting enzyme 2 (ACE2), a key counter regulator of the renin-angiotensin system (RAS), is the main entry gate of SARS-CoV-2 into human host cells and an established drug target to prevent heart failure. In fact, ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid antagonists may augment ACE2 levels to protect organs from angiotensin II overload. Elevated ACE2 expression on the host cell surface might facilitate viral entrance, at the same time sudden nonadherence to these medications triggers MACEs. Hence, safety issues in the use of RAS inhibitors in COVID-19 patients with cardiac dysfunction remain an unsolved dilemma and need paramount attention. Although ACE2 generally plays an adaptive role in both healthy subjects and patients with systolic and/or diastolic dysfunction, we conducted a literature appraisal on its maladaptive role. Understanding the exact role of ACE2 in COVID-19 patients at risk of heart failure is needed to safely manage RAS inhibitors in frail and non-frail critically ill patients.
| S-EPMC7447089 | biostudies-literature
Project description:BackgroundGlobally, the current medical emergency for novel coronavirus 2019 (COVID-19) leads to respiratory distress syndrome and death.PurposeThis review highlighted the effect of COVID-19 on systemic multiple organ failure syndromes. This review is intended to fill a gap in information about human physiological response to COVID-19 infections. This review may shed some light on other potential mechanisms and approaches in COVID -19 infections towards systemic multiorgan failure syndromes.FindingSARS-CoV-2 intervened mainly in the lung with progression to pneumonia and acute respiratory distress syndrome (ARDS) via the angiotensin-converting enzyme 2(ACE2) receptor. Depending on the viral load, infection spread through the ACE2 receptor further to various organs such as heart, liver, kidney, brain, endothelium, GIT, immune cell, and RBC (thromboembolism). This may be aggravated by cytokine storm with the extensive release of proinflammatory cytokines from the deregulating immune system.ConclusionThe widespread and vicious combinations of cytokines with organ crosstalk contribute to systemic hyper inflammation and ultimately lead to multiple organ dysfunction (Fig. 1). This comprehensive study comprises various manifestations of different organs in COVID-19 and may assist the clinicians and scientists pertaining to a broad approach to fight COVID 19.
| S-EPMC7500408 | biostudies-literature
Project description:The angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis plays a significant role in regulating myocardial remodeling and the development of heart failure (HF), with ACE2 being the primary focus. However, contemporary understanding of the membrane-bound form of the human ACE2 protein remains insufficient. The purpose of this study was to determine the expression of ACE2 protein in different cells of the left ventricular myocardium in non-diseased hearts and at various stages of ischemic HF. A total of 103 myocardial tissue samples from the left ventricle underwent quantitative and semi-quantitative immunohistochemical analysis. Upon assessing ACE2 immunostaining in all myocardial cells through unselective digital image analysis, there was no change in the stage A HF group. Nevertheless, the expression of ACE2 membrane protein in cardiomyocytes showed a tendency to increase, while non-cardiomyocyte ACE2 expression decreased significantly (p < 0.001). In the stage B HF group, the intensity of ACE2 immunostaining continued to increase with rising cardiomyocyte ACE2 expression (p < 0.001). Non-cardiomyocyte expression, in contrast, remained similar to that observed in the stage A HF group. In the stages C/D HF group, ACE2 expression reached its highest level in cardiomyocytes (p < 0.001), while ACE2 expression in non-cardiomyocytes was the lowest (p < 0.001). These changes in ACE2 protein levels are associated with left ventricular remodeling in ischemic HF.
| S-EPMC10743033 | biostudies-literature
Project description:AimsThe current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.Methods and resultsWe measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.ConclusionIn two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.
| S-EPMC7239195 | biostudies-literature
Project description:The pandemic of coronavirus disease 2019 (COVID-19) is a global health emergency that poses a significant threat to world people's health. This outbreak causes major challenges to healthcare systems. Given the lack of effective treatments or vaccine for it, the identification of novel and safe drugs against COVID-19 infection is an urgent need. Angiotensin-converting enzyme 2 (ACE2) is not only an entry receptor of the SARS-CoV-2 virus, the virus that causes COVID-19, but also can protect from lung injury. In this view, we highlighted potential approaches to address ACE2-mediated SARS-CoV-2 virus, including 1) delivering an excessive soluble form of ACE2 (recombinant human ACE2: rhACE2) and 2) inhibition of the interaction between SARS-CoV-2 virus and ACE2 by some compounds with competitive effects (morphine and codeine). Further clinical trials in this regard can reveal a more definite conclusion against the COVID-19 disaster.
| S-EPMC7214324 | biostudies-literature
Project description:The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications.
| S-EPMC7796300 | biostudies-literature
Project description:RationaleHypertension, obesity and diabetes are major risk factors associated with morbidities underlying COVID-19 infections. Regression analysis correlated presence of ACE insertion/deletion (I/D) polymorphism to COVID-19 incidence and mortality. Furthermore, COVID-19 prevalence correlated to allele frequency of angiotensin-converting enzyme (ACE) deletion (D) polymorphism within the European population.ObjectiveHomozygous ACE deletion polymorphism is associated with increase in ACE and angiotensin II (Ang-II), sustained levels can result in inflammation, fibrosis and organ damage. The ACE DD polymorphism is also associated with hypertension, acute respiratory distress and diabetic nephropathy, all considered high risk for COVID-19 infection and outcomes. The study objective was to describe a biological framework associating ethnic prevalence of ACE deletion polymorphism to COVID-19 comorbidities providing rationale for therapeutic utility of ACE-I/ARBs to improve outcomes.Method and resultsThe Allele Frequency Database (ALFRED) was queried for frequency of rs4646994 representing ACE I/D polymorphism. In a total of 349 worldwide population samples, frequency of ACE D allele was higher in European, Asian, and Africans cohorts. In the USA, the frequency of ACE D allele was higher in non-Hispanic Black compared with non-Hispanic White and Mexican Americans.ConclusionCOVID-19 binding mediated reduction/inactivation of ACE-II can increase ACE/Ang-II signalling pathway and related pathologies. The presence of ACE DD polymorphism with COVID-19 infection likely augments ACE/Ang-II activities, increasing severity of COVID-19 morbidities and impacts outcomes. Thus, ethnic prevalence of ACE DD polymorphism can explain in part the severity of COVID-19 morbidity providing rationale for the use of ACE-I/ARBs to improve outcomes.
| S-EPMC7478439 | biostudies-literature
Project description:On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, and the reality of the situation has finally caught up to the widespread reach of the disease. The presentation of the disease is highly variable, ranging from asymptomatic carriers to critical COVID-19. The availability of angiotensin-converting enzyme 2 (ACE2) receptors may reportedly increase the susceptibility and/or disease progression of COVID-19. Comorbidities and risk factors have also been noted to increase COVID-19 susceptibility. In this paper, we hereby review the evidence pertaining to ACE2's relationship to common comorbidities, risk factors, and therapies associated with the susceptibility and severity of COVID-19. We also highlight gaps of knowledge that require further investigation. The primary comorbidities of respiratory disease, cardiovascular disease, renal disease, diabetes, obesity, and hypertension had strong evidence. The secondary risk factors of age, sex, and race/genetics had limited-to-moderate evidence. The tertiary factors of ACE inhibitors and angiotensin II receptor blockers had limited-to-moderate evidence. Ibuprofen and thiazolidinediones had limited evidence.
| S-EPMC7938645 | biostudies-literature