Attenuation of Smooth Muscle Cell Phenotypic Switching by Angiotensin 1-7 Protects against Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Activation of the renin-angiotensin system, and resultant angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of angiotensin (Ang) 1-7 on a murine model of TAA. Male 8-10-week-old ApoEKO mice were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). ApoEKO mice developed advanced TAA in response to four weeks of Ang II infusion. Echocardiographic and histological analyses demonstrated increased aortic dilatation, excessive structural remodelling, perivascular fibrosis, and inflammation in the thoracic aorta. Ang 1-7 infusion led to attenuation of pathological phenotypic alterations associated with Ang II-induced TAA. Smooth muscle cells (SMCs) isolated from adult murine thoracic aorta exhibited excessive mitochondrial fission, oxidative stress, and hyperproliferation in response to Ang II. Treatment with Ang 1-7 resulted in inhibition of mitochondrial fragmentation, ROS generation, and hyperproliferation. Gene expression profiling used for characterization of the contractile and synthetic phenotypes of thoracic aortic SMCs revealed preservation of the contractile phenotype with Ang 1-7 treatment. In conclusion, Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA.

Tryptophan degradation enzymes and Angiotensin (1-7) expression in human placenta.

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The intrauterine renin-angiotensin system is also involved in the progression of a healthy pregnancy. Angiotensin(1-7) maintains the integrity of fetal membranes via counteracting the pro-inflammatory actions of Angiotensin II. No data are available on placental Angiotensin(1-7) co-expression with TDO. We aimed to characterize TDO mRNA expression and its localization in different areas of the placenta of physiological pregnancies delivered at term; its co-expression with Angiotensin(1-7) and its correlation with the plasma kynurenine/tryptophan (Kyn/Trp) ratio was investigated. This prospective observational study included a nonconsecutive series of 20 singleton uncomplicated pregnancies delivered vaginally. TDO mRNA was expressed in both maternal and fetal sides of the placentas and TDO protein also in the villi and it was co-expressed with IDO1 in almost half of the placental cells at these sites. The percentage of TDO+ and IDO1+ cells appeared to be influenced by maternal pre-gestational smoking and newborn weight. A strong correlation was found between the percentage of TDO+ and IDO1+ cells in the villi. TDO+ cells also expressed Angiotensin(1-7), with a higher percentage on the fetal side and in the villi compared to the maternal one. Kyn/Trp plasma ratio was not correlated with IDO and TDO expression nor with the patient's characteristics. Collectively, our data indicate that TDO is detectable in placental tissue and is co-expressed with IDO and with Angiotensin(1-7)+ on the fetal side and in the villi.

Renin-Angiotensin System in Huntington's Disease: Evidence from Animal Models and Human Patients.

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein.

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.

Diminazene Aceturate Stabilizes Atherosclerotic Plaque and Attenuates Hepatic Steatosis in apoE-Knockout Mice by Influencing Macrophages Polarization and Taurine Biosynthesis.

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE-/- mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.

The angiotensin converting enzyme 2 (ACE2) system in the brain: possible involvement in Neuro-Covid.

The brain has its own intrinsic renin-angiotensin system (RAS) with all its components present in the central nervous system (CNS). Recent data demonstrate that also the main components of the angiotensin concerting enzyme 2 (ACE2) system (at least ACE2 itself, as well as the biologically active angiotensin (1-7) and its cognate receptor Mas) are expressed in the brain. Aside from these members, alamadine and MrgD are discussed as further members that have neuro-active roles in the CNS. Little is known about the possible functions of MrgD within the brain. Concerning angiotensin (1-7) acting through the Mas receptor, data were accumulating that this system is involved in numerous processes contributing to neuronal plasticity and even learning and memory. Malfunctions in the brain ACE2 system are associated with disturbances in neuronal plasticity. Since SARS-CoV-2 has a high affinity towards ACE2, Neuro-Covid may directly or indirectly depend on a disturbed balance in the ACE2 derived angiotensin system in the brain. Since the ACE2 system in the brain is far from being understood, a deeper understanding of e.g. the angiotensin (1-7) / Mas system is needed, especially with regard to the roles of angiotensin (1-7) in neuronal plasticity.

Renin-angiotensin system and inflammation update.

The most classical view of the renin-angiotensin system (RAS) emphasizes its role as an endocrine regulator of sodium balance and blood pressure. However, it has long become clear that the RAS has pleiotropic actions that contribute to organ damage, including modulation of inflammation. Angiotensin II (Ang II) activates angiotensin type 1 receptors (AT1R) to promote an inflammatory response and organ damage. This represents the pathophysiological basis for the successful use of RAS blockers to prevent and treat kidney and heart disease. However, other RAS components could have a built-in capacity to brake proinflammatory responses. Angiotensin type 2 receptor (AT2R) activation can oppose AT1R actions, such as vasodilatation, but its involvement in modulation of inflammation has not been conclusively proven. Angiotensin-converting enzyme 2 (ACE2) can process Ang II to generate angiotensin-(1-7) (Ang-(1-7)), that activates the Mas receptor to exert predominantly anti-inflammatory responses depending on the context. We now review recent advances in the understanding of the interaction of the RAS with inflammation. Specific topics in which novel information became available recently include intracellular angiotensin receptors; AT1R posttranslational modifications by tissue transglutaminase (TG2) and anti-AT1R autoimmunity; RAS modulation of lymphoid vessels and T lymphocyte responses, especially of Th17 and Treg responses; interactions with toll-like receptors (TLRs), programmed necrosis, and regulation of epigenetic modulators (e.g. microRNAs and bromodomain and extraterminal domain (BET) proteins). We additionally discuss an often overlooked effect of the RAS on inflammation which is the downregulation of anti-inflammatory factors such as klotho, peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), transient receptor potential ankyrin 1 (TRPA1), SNF-related serine/threonine-protein kinase (SNRK), serine/threonine-protein phosphatase 6 catalytic subunit (Ppp6C) and n-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Both transcription factors, such as nuclear factor κB (NF-κB), and epigenetic regulators, such as miRNAs are involved in downmodulation of anti-inflammatory responses. A detailed analysis of pathways and targets for downmodulation of anti-inflammatory responses constitutes a novel frontier in RAS research.

Prorenin periconceptionally and in pregnancy: Does it have a physiological role?

Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.

Novel roles of the renal angiotensin-converting enzyme.

The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.

Angiotensin receptors in the kidney and vasculature in hypertension and kidney disease.

Kidney disease, blood pressure determination, hypertension pathogenesis, and the renin-angiotensin system (RAS) are inextricably linked. Hence, understanding the RAS is pivotal to unraveling the pathophysiology of hypertension and the determinants to maintaining normal blood pressure. The RAS has been the subject of intense investigation for over a century. Moreover, medications that block the RAS are mainstay therapies in clinical medicine and have been shown to reduce morbidity and mortality in patients with diabetes, cardiovascular, and kidney diseases. The main effector peptide of the RAS is the interaction of the octapeptide- Ang II with its receptor. The type 1 angiotensin receptor (AT1R) is the effector receptor for Ang II. These G protein-coupled receptors (GPCRs) are ubiquitously expressed in a variety of cell lineages and tissues relevant to cardiovascular disease throughout the body. The advent of cell specific deletion of genes using Cre LoxP technology in mice has allowed for the identification of discreet actions of AT1Rs in blood pressure control and kidney disease. The kidney is one of the major targets of the RAS, which is responsible in maintaining fluid, electrolyte balance, and blood pressure. In this review we will discuss the role of AT1Rs in the kidney, vasculature, and immune cells and address their effects on hypertension and kidney disease.

Metabolism of angiotensin peptides by angiotensin converting enzyme 2 (ACE2) and analysis of the effect of excess zinc on ACE2 enzymatic activity.

After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the renin-angiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT1 Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-Asp1Ang II, 2-8 heptapeptide) and Ang IV (des-Asp1des-Arg2Ang II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest Km) for Ang III, followed by Ang II ∼ Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 µM. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.

Angiotensin-(1-7), Angiotensin-Converting Enzyme 2 and Mas Receptor in Rat Polycystic Ovaries.

BACKGROUND: Hyperandrogenism is a pivotal mediator in the pathogenesis of the polycystic ovary syndrome (PCOS), but the mechanisms of androgen excess in this condition are not fully understood. Angiotensin (Ang)-(1-7) is an active peptide of the renin-angiotensin system (RAS) that stimulates ovarian follicular growth and testosterone release in vitro. OBJECTIVE: To investigate whether Ang-(1-7), its receptor Mas and angiotensin-converting enzyme 2 (ACE2), the enzyme that converts Ang II into Ang-(1-7), are expressed in rat polycystic ovaries (PCO) and thus if this peptide system might be associated with excess androgen production in PCO. METHODS: A rat model that shares some features of PCOS such as disruption of folliculogenesis and multiple ovarian cyst formation was used in the study. RESULTS: We found reduced levels of Ang-(1-7) and Mas receptor in PCO compared to normal ovaries. Also, ACE2 mRNA expression was reduced in PCO compared to ovaries of control rats (p < 0.05). PCO had high levels of estrogen and testosterone and increased mRNA for upstream enzymes of the steroidogenic cascade, but not of P450 aromatase. CONCLUSION: These findings suggest that the ovarian ACE2-Ang-(1-7)-Mas receptor axis is inhibited and therefore may not be a co-factor of excess testosterone production in rat PCO.

LP2, the first lanthipeptide GPCR agonist in a human pharmacokinetics and safety study.

Introduction of a lanthionine into a peptide may enhance target affinity, target specificity and proteolytic resistance. This manuscript reports preclinical safety studies and the first-in-human study with the lanthipeptide AT2R agonist LP2, a structural analog of cAng-(1-7), whose N-terminus was protected against aminopeptidases by the presence of a d-lysine. None of the preclinical studies, including an in vitro multitarget panel, behavioral, respiratory and cardiovascular measurements, genotoxicity and toxicity studies in rat and dog, posed any safety concern. Due to lack of toxicity the maximum tolerated dose was not reached neither in rat nor in dog. In the human dose escalation study, healthy male volunteers received a single 1 mL subcutaneous injection (0.001 mg, 0.01 mg or 0.1 mg) of LP2 or matching placebo. In contrast to angiotensin II which has a T1/2 in plasma of < 1 min, LP2 has a T1/2 of approximately 2.1-2.6 hours. The fraction of the dose excreted unchanged in urine ranged from 84.73 ± 10.4 % at a dose of 0.001 mg to 66.4 ± 3.9 % at 0.1 mg. There were no deaths, serious adverse events or subject withdrawals as a result of an adverse event. The incidence of adverse events was 16.7 %; each was mild in severity. One adverse event, peripheral coldness, was considered to be possibly related to LP2 at 0.001 mg LP2. None of the results was considered to pose a clinically relevant safety concern. This study supports the potential for the therapeutic use of lanthipeptides.

The Angiotensin-(1-12)/Chymase axis as an alternate component of the tissue renin angiotensin system.

The identification of an alternate extended form of angiotensin I composed of the first twelve amino acids at the N-terminal of angiotensinogen has generated new knowledge of the importance of noncanonical mechanisms for renin independent generation of angiotensins. The human sequence of the dodecapeptide angiotensin-(1-12) [N-Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8-His9-Leu10-Val1-Ile12-COOH] is an endogenous substrate that in the rat has been documented to be present in multiple organs including the heart, brain, kidney, gut, adrenal gland, and the bone marrow. Newer studies have confirmed the existence of Ang-(1-12) as an Ang II-forming substrate in the blood and heart of normal and diseased patients. Studies to-date document that angiotensin II generation from angiotensin-(1-12) does not require renin participation while chymase rather than angiotensin converting enzyme shows high catalytic activity in converting this tissue substrate into angiotensin II directly.

The renin-angiotensin system in COVID-19: Why ACE2 targeting by coronaviruses produces higher mortality in elderly hypertensive patients?

This renin-angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues. Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS-related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle. RAS and stress accumulation: While prorenin is active after binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance. Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws.

Upregulation of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis by a combination of Yinyanghuo (Herba Epimedii Brevicornus) and Cheqianzi (Semen Plantaginis) improves erectile function in spontaneously hypertensive rats.

OBJECTIVE: To evaluate the effects of a combination of Yinyanghuo (Herba Epimedii Brevicornus) (HEB) and Cheqianzi (Semen Plantaginis) (SP) on erectile dysfunction caused by essential hypertension in spontaneously hypertensive rats (SHRs), and to elucidate the role of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor (ACE2/Ang [1-7]/Mas receptor) axis in this process. METHODS: A total of 24 SHRs were randomly assigned to three groups: SHR-control, low-dose (12.5 g/kg) and high-dose (25 g/kg) HEB+SP (HEBSP). Eight Wistar-Kyoto rats were used as normal controls. HEBSP was administered by oral gavage for 28 d. Erectile function was measured once a week using the Heaton test. After 4 weeks of treatment, the corpus cavernosum was harvested from each rat to measure nitric oxide (NO), nitric oxide synthase (eNOS) and Ang (1-7) levels, as well as ACE2, Mas receptor and neuronal nitric oxide synthase (nNOS) protein expression. RESULTS: After 4 weeks of treatment, HEBSP significantly increased erectile function in the treated group compared with SHR-control group (P < 0.01). Additionally, HEBSP treatment significantly increased cavernosal levels of Ang (1-7), eNOS and NO. Moreover, HEBSP significantly elevated the expression levels of ACE2, Mas receptor and nNOS. These beneficial effects were elevated in the high-dose HEBSP group. CONCLUSION: HEBSP improved erectile function in SHRs by upregulating the ACE2/Ang (1-7)/Mas receptor axis, eNOS and nNOS pathways.

ACE2 modulates glucose homeostasis through GABA signaling during metabolic stress.

The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (A1-7)/MAS axis and glutamate decarboxylase 67 (GAD67)/gamma-aminobutyric acid (GABA) signal both exist in the islet and play important roles in regulating blood glucose metabolism. It has been reported that the activation of ACE2 in the brain increases GABA expression to improve biological effects; however, it is unclear whether there is functional correlation between the ACE2/A1-7/MAS axis and GAD67/GABA signal in the islet. In this study, we showed that the ACE2/A1-7/MAS and GABA signaling systems decreased in the islet of different metabolic stress models. In ACE2-knockout mice, we found that GAD67 and GABA expression decreased significantly, which was reversed by exogenous administration of A1-7. Furthermore, A1-7 mediated PDX1 and AKT activation was inhibited by allylglycine (a specific GAD67 inhibitor) in MIN6 cells. Moreover, giving A1-7 and GABA could significantly reduce beta-cell dedifferentiation and improved glucose metabolism during metabolic stress in vivo and in vitro. In conclusion, our study reveals that the ACE2/A1-7/MAS axis improves beta-cell function through regulating GAD67/GABA signal in beta cells and that up-regulating the ACE2/A1-7/MAS axis and GABA signals delays the development of obesity-induced diabetes.

A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19.

The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS.

Angiotensin-â ¡ and angiotensin-(1-7) imbalance affects comorbidity of depression and coronary heart disease.

A large body of evidence suggests a relationship between depression and coronary heart disease (CHD). Angiotensin-Ⅱ (Ang-Ⅱ) and angiotensin-(1-7) [Ang-(1-7)] are considered to exert biological effects in both conditions. Here, we aimed to determine the role of Ang-Ⅱ and Ang-(1-7) in the occurrence of comorbid depression in patients with CHD. Our study included 214 CHD patients and 100 matched healthy controls. Serum Ang-Ⅱ and Ang-(1-7) levels were assessed by ELISA, and the depression symptoms were evaluated by the nine-item Patient Health Questionnaire (PHQ-9). Linear regression and correlation analyses were used to estimate the associations between PHQ-9 scores and Ang-Ⅱ and Ang-(1-7) serum levels. Six single-nucleotide polymorphisms (SNPs) spanning the angiotensin converting enzyme 2 (ACE2) and MAS1 genes were genotyped. The associations between SNPs and depression risk in CHD patients were examined using logistic regression analysis with adjustment for age and gender. Decreased Ang-(1-7) (P < 0.05) and an elevated Ang-Ⅱ/Ang-(1-7) ratio (P < 0.01) were observed in CHD patients with depression compared to CHD patients without depression. PHQ-9 scores were negatively correlated with Ang-(1-7) level (r=-0.44, P < 0.01) and positively correlated with the Ang-Ⅱ/Ang-(1-7) ratio (r = 0.33, P < 0.05). Furthermore, carriers of risk allele T for CHD with depression had significantly higher PHQ-9 scores (P < 0.05), lower Ang-(1-7) level (P < 0.01), and higher Ang-Ⅱ/Ang-(1-7) ratio (P < 0.05) than those CC carriers. Collectively, our results firstly showed that Ang-(1-7) serum level in CHD patients may protect against comorbid depression. Moreover, the imbalance between Ang-Ⅱ and Ang-(1-7) may contribute to depression in CHD patients.