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.
The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin ...converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.
ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent functiona negative regulator of the renin-angiotensin system, facilitator of amino ...acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.
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.
The vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, ...and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly polarized receptor distribution contributed to distinct signaling patterns: VEGFR2, which was found to be predominantly abluminal, mediated increased permeability via p38; in contrast, luminal VEGFR1 led to Akt activation and facilitated cytoprotection. Importantly, such differential apicobasal signaling and VEGFR distribution were found in the microvasculature of brain and retina but not lung, indicating that endothelial cells at blood-neural barriers possess specialized signaling compartments that assign different functions depending on whether an agonist is tissue or blood borne.
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•At blood-neural barriers, only abluminal (tissue-side) VEGF-A induces permeability•Most VEGFR1 is localized on the luminal face of neural microvascular endothelium•Most VEGFR2 is localized on the abluminal face of neural microvascular endothelium•Luminal VEGFR1 stimulates Akt; abluminal VEGFR2 induces permeability via p38
Hudson et al. show that the microvascular endothelium of blood-neural barriers uses functional polarity of signaling to compartmentalize responses to vasoactive stimuli. VEGFR2, predominantly expressed on the abluminal face of the endothelium, mediates p38 and vascular permeability. Luminally polarized VEGFR1 activates Akt but does not contribute to permeability.
A healthy gut microbiota is essential in maintaining the human body in a homeostatic state by its functions in digestion and immune tolerance. Under states of aberrant microbial composition or ...function (dysbiosis), the gut microbiota induces systemic inflammation that can lead to the onset of many diseases. In this review, we describe some evidence, largely from rodent studies, that supports the possible role of a dysbiotic gut microbiota in the onset and exacerbation of ocular diseases, primarily diabetic retinopathy, age-related macular degeneration, choroidal neovascularization, and uveitis. Furthermore, we examine several potential therapeutic measures that show promise in restoring the gut microbiota to a eubiotic state, preventing the aforementioned disease pathologies.
Hyperglycemia-Induced Reactive Oxygen Species Toxicity to Endothelial Cells Is Dependent on Paracrine Mediators
Julia V. Busik 1 ,
Susanne Mohr 2 and
Maria B. Grant 3
1 Department of Physiology, ...Michigan State University, East Lansing, Michigan
2 Department of Medicine, Case Western Reserve University, Cleveland, Ohio
3 Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
Corresponding author: Maria B. Grant, grantma{at}ufl.edu
Abstract
OBJECTIVE— This study determined the effects of high glucose exposure and cytokine treatment on generation of reactive oxygen species
(ROS) and activation of inflammatory and apoptotic pathways in human retinal endothelial cells (HRECs).
RESEARCH DESIGN AND METHODS— Glucose consumption of HRECs, human retinal pigment epithelial cells (HRPEs), and human Müller cells (HMCs) under elevated
glucose conditions was measured and compared with cytokine treatment. Production of ROS in HRECs was examined using 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein
diacetate (CM-H 2 DCFDA), spin-trap electron paramagnetic resonance, and MitoTracker Red staining after high glucose and cytokine treatment.
The activation of different signaling cascades, including the mitogen-activated protein kinase pathways, tyrosine phosphorylation
pathways, and apoptosis by high glucose and cytokines in HRECs, was determined.
RESULTS— HRECs, in contrast to HRPEs and HMCs, did not increase glucose consumption in response to increasing glucose concentrations.
Exposure of HRECs to 25 mmol/l glucose did not stimulate endogenous ROS production, activation of nuclear factor-κB (NF-κB),
extracellular signal–related kinase (ERK), p38 and Jun NH 2 -terminal kinase (JNK), tyrosine phosphorylation, interleukin (IL)-1β, or tumor necrosis factor-α (TNF-α) production and only
slightly affected apoptotic cell death pathways compared with normal glucose (5 mmol/l). In marked contrast, exposure of HRECs
to proinflammatory cytokines IL-1β or TNF-α increased glucose consumption, mitochondrial superoxide production, ERK and JNK
phosphorylation, tyrosine phosphorylation, NF-κB activation, and caspase activation.
CONCLUSIONS— Our in vitro results indicate that HRECs respond to cytokines rather than high glucose, suggesting that in vivo diabetes–related
endothelial injury in the retina may be due to glucose-induced cytokine release by other retinal cells and not a direct effect
of high glucose.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 April 2008.
J.V.B. and S.M. contributed equally to this study.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted April 9, 2008.
Received October 26, 2007.
DIABETES
Our hypothesis is that diabetes leads to loss of diurnal oscillatory rhythms in gut microbiota altering circulating metabolites. We performed an observational study where we compared diurnal changes ...of the gut microbiota with temporal changes of plasma metabolites. Metadata analysis from bacterial DNA from fecal pellets collected from 10-month old control (db/m) and type 2 diabetic (db/db) mice every 4 h for a 24-h period was used for prediction analysis. Blood plasma was collected at a day and night time points and was used for untargeted global metabolomic analysis. Feeding and activity behaviors were recorded. Our results show that while diabetic mice exhibited feeding and activity behavior similar to control mice, they exhibited a loss of diurnal oscillations in bacteria of the genus
,
,
,
and a phase shift in the oscillations of
, proteobacteria, and actinobacteria. Analysis of the circulating metabolites showed alterations in the diurnal pattern of metabolic pathways where bacteria have been implicated, such as the histidine, betaine, and methionine/cysteine pathway, mitochondrial function and the urea cycle. Functional analysis of the differential microbes revealed that during the day, when mice are asleep, the microbes of diabetic mice were enriched in processing carbon and pyruvate metabolic pathways instead of xenobiotic degradation as was observed for control mice. Altogether, our study suggests that diabetes led to loss of rhythmic oscillations of many gut microbiota with possible implications for temporal regulation of host metabolic pathways.
p62 is a scaffolding adaptor implicated in the clearance of protein aggregates by autophagy. Reactive oxygen species (ROS) can either stimulate or inhibit NFκB-mediated gene expression influencing ...cellular fate. We studied the effect of hydrogen peroxide (H2O2)-mediated oxidative stress and NFκB signaling on p62 expression in the retinal pigment epithelium (RPE) and investigated its role in regulation of autophagy and RPE survival against oxidative damage. Cultured human RPE cell line ARPE-19 and primary human adult and fetal RPE cells were exposed to H2O2-induced oxidative stress. The human apolipoprotein E4 targeted-replacement (APOE4) mouse model of AMD was used to study expression of p62 and other autophagy proteins in the retina. p62, NFκB p65 (total, phosphorylated, nuclear and cytoplasmic) and ATG10 expression was assessed by mRNA and protein analyses. Cellular ROS and mitochondrial superoxide were measured by CM-H2DCFDA and MitoSOX staining respectively. Mitochondrial viability was determined using MTT activity. qPCR-array system was used to investigate autophagic genes affected by p62. Nuclear and cytoplasmic levels of NFκB p65 were evaluated after cellular fractionation by Western blotting. We report that p62 is up-regulated in RPE cells under H2O2-induced oxidative stress and promotes autophagic activity. Depletion of endogenous p62 reduces autophagy by downregulation of ATG10 rendering RPE more susceptible to oxidative damage. NFκB p65 phosphorylation at Ser-536 was found to be critical for p62 upregulation in response to oxidative stress. Proteasome inhibition by H2O2 causes p62-NFκB signaling as antioxidant pre-treatment reversed p62 expression and p65 phosphorylation when RPE was challenged by H2O2 but not when by Lactacystin. p62 protein but not RNA levels are elevated in APOE4-HFC AMD mouse model, suggesting reduction of autophagic flux in disease conditions. Our findings suggest that p62 is necessary for RPE cytoprotection under oxidative stress and functions, in part, by modulating ATG10 expression. NFκB p65 activity may be a critical upstream initiator of p62 expression in RPE cells under oxidative stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The metabolically active retina obtains essential lipids by endogenous biosynthesis and from the systemic circulation. Clinical studies provide limited and sometimes conflicting evidence as to the ...relationships between circulating lipid levels and the development and progression of diabetic retinopathy in people with diabetes. Cardiovascular-system-focused clinical trials that also evaluated some retinal outcomes demonstrate the potential protective power of lipid-lowering therapies in diabetic retinopathy and some trials with ocular primary endpoints are in progress. Although triacylglycerol-lowering therapies with fibrates afforded some protection against diabetic retinopathy, the effect was independent of changes in traditional blood lipid classes. While systemic LDL-cholesterol lowering with statins did not afford protection against diabetic retinopathy in most clinical trials, and none of the trials focused on retinopathy as the main outcome, data from very large database studies suggest the possible effectiveness of statins. Potential challenges in these studies are discussed, including lipid-independent effects of fibrates and statins, modified lipoproteins and retinal-specific effects of lipid-lowering drugs. Dysregulation of retinal-specific cholesterol metabolism leading to retinal cholesterol accumulation and potential formation of cholesterol crystals are also addressed.
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