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Circulation Research Feb 2020Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction...
Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress.
RATIONALE
Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.
OBJECTIVE
We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension.
METHODS AND RESULTS
To test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects.
CONCLUSIONS
We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.
Topics: Angiotensin II; Animals; Desoxycorticosterone Acetate; Endothelium, Vascular; Essential Hypertension; Female; Heart; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria, Heart; Mitochondrial Proteins; Myocardium; Oxidative Stress; Sirtuin 3
PubMed: 31852393
DOI: 10.1161/CIRCRESAHA.119.315767 -
Circulation Research Jan 2024T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of...
BACKGROUND
T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear.
METHODS
Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmn/CD4), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmn/Foxp3), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development.
RESULTS
LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects.
CONCLUSIONS
LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.
Topics: Animals; Humans; Mice; Acetates; Angiotensin II; CD4-Positive T-Lymphocytes; Desoxycorticosterone; Hypertension; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; TNF Receptor-Associated Factor 6
PubMed: 38047378
DOI: 10.1161/CIRCRESAHA.123.322835 -
Cardiovascular Research Oct 2023Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence...
AIMS
Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling.
METHODS AND RESULTS
Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure.
CONCLUSIONS
Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.
Topics: Humans; Mice; Animals; Heart Failure; Desoxycorticosterone Acetate; Stroke Volume; Hypertension; Cardiomyopathies; Myeloid Cells; Leukocytes; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37314125
DOI: 10.1093/cvr/cvad093 -
Journal of Veterinary Internal Medicine Mar 2023Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse.
BACKGROUND
Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse.
OBJECTIVE
To describe cats with PH with a focus on long-term treatment.
ANIMALS
Eleven cats with naturally occurring PH.
METHODS
Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months.
RESULTS
Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively.
CONCLUSIONS AND CLINICAL IMPORTANCE
Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.
Topics: Cats; Animals; Dogs; Prednisolone; Dog Diseases; Adrenal Insufficiency; Desoxycorticosterone; Addison Disease; Cat Diseases
PubMed: 36809682
DOI: 10.1111/jvim.16658 -
Acta Pharmacologica Sinica Jun 2023Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological...
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg·d) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of β-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.
Topics: Animals; Mice; Cardiomegaly; Cardiomyopathies; Desoxycorticosterone Acetate; Fibrosis; Heart Failure; Myocytes, Cardiac; Stroke Volume; Wnt Signaling Pathway
PubMed: 36473990
DOI: 10.1038/s41401-022-01025-y -
European Review For Medical and... Aug 2023The aim of this study was to investigate the protective effect and mechanism of action (MOA) of Qiliqiangxin capsule (QL) in the deoxycorticosterone acetate (DOCA)...
OBJECTIVE
The aim of this study was to investigate the protective effect and mechanism of action (MOA) of Qiliqiangxin capsule (QL) in the deoxycorticosterone acetate (DOCA) salt-induced rat heart failure with preserved ejection fraction (HFpEF) model.
MATERIALS AND METHODS
Nono-nephrectomy sixty Sprague Dawley (SD) rats received DOCA salt injection and 1% saline in drinking water for 4 weeks and were randomly divided into four groups on average: Model group (n=15), Sac/Val group (Sacubitril Valsartan 0.02 g/kg, n=15), QL-L group (Qiliqiangxin 0.25 g/kg, n=15) and QL-H group (Qiliqiangxin 1 g/kg, n=15). Another Normal group was set (n=15). Blood pressure, N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac index, echocardiography, and hemodynamics were measured to evaluate heart function. Masson and Wheat germ agglutinin (WGA) staining was performed to observe the fibrosis deposition and the cross-sectional area (CSA) of cardiomyocytes. The concentration levels of the serum cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and IL-10 inflammatory factors, were detected by ELISA; matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), transforming growth factor-β1 (TGF-β1), nuclear factor-κB (NF-κB), Smad homologue 2 (Smad2) and Smad homologue 3 (Smad3) expression were detected by Western-blot.
RESULTS
Compared with the Model group, QL treatment significantly ameliorated the heart function in DOCA salt-induced rat HFpEF model, showing a decrease in cardiac index, an increase of the EF and E/A ratio, a reduction in the left ventricular anterior/posterior wall (LVAW/LVPW), in the time contraction of isovolumic diastolic time (IVRT), -dP/dt Max, and Tau, and the decrease of serum NT-ProBNP. Masson and WGA staining indicated that QL inhibited the fibrosis deposition and the myocardial hypertrophy compared with the Model group, which was consistent in reducing the protein expression levels of cardiac remodeling such as TGF-β1, MMP2, MMP9, Smad2, and Smad3. Moreover, QL treatment inhibited the expression of NF-κB in the heart tissues and decreased the serum concentration of pro-inflammatory cytokines TNF-α and IL-2, instead, increasing the IL-10 concentration.
CONCLUSIONS
QL improved the cardiac function and inhibited the myocardial fibrosis in DOCA salt-induced rat HFpEF by improving diastolic dysfunction, preventing left ventricular hypertrophy, and ameliorating the inflammatory responses model in DOCA salt-induced rat HFpEF model.
Topics: Rats; Animals; Matrix Metalloproteinase 2; Interleukin-10; Desoxycorticosterone Acetate; Matrix Metalloproteinase 9; Transforming Growth Factor beta1; Heart Failure; NF-kappa B; Tumor Necrosis Factor-alpha; Ventricular Remodeling; Rats, Sprague-Dawley; Stroke Volume; Myocytes, Cardiac; Cytokines
PubMed: 37606135
DOI: 10.26355/eurrev_202308_33298 -
JCI Insight Jul 2023Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to...
Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to participate in P2ry2 effects on blood pressure. To isolate the role of the kidneys in P2ry2 effects on blood pressure and to reveal the molecular and cellular mechanisms of this action, we test here the necessity of the P2ry2 and the sufficiency of Gq-dependent signaling in renal principal cells to the regulation of the epithelial Na+ channel (ENaC), sodium excretion, and blood pressure. Activating P2ry2 in littermate controls but not principal cell-specific P2ry2-knockout mice decreased the activity of ENaC in renal tubules. Moreover, deletion of P2ry2 in principal cells abolished increases in sodium excretion in response to stimulation of P2ry2 and compromised the normal ability to excrete a sodium load. Consequently, principal cell-specific knockout of P2ry2 prevented decreases in blood pressure in response to P2ry2 stimulation in the deoxycorticosterone acetate-salt (DOCA-salt) model of hypertension. In wild-type littermate controls, such stimulation decreased blood pressure in this model of hypertension by promoting a natriuresis. Pharmacogenetic activation of Gq exclusively in principal cells using targeted expression of Gq-designer receptors exclusively activated by designer drugs and clozapine N-oxide decreased the activity of ENaC in renal tubules, promoting a natriuresis that lowered elevated blood pressure in the DOCA-salt model of hypertension. These findings demonstrate that the kidneys play a major role in decreasing blood pressure in response to P2ry2 activation and that inhibition of ENaC activity in response to P2ry2-mediated Gq signaling lowered blood pressure by increasing renal sodium excretion.
Topics: Mice; Animals; Blood Pressure; Receptors, Purinergic P2Y2; Desoxycorticosterone Acetate; Sodium; Hypertension; Mice, Knockout
PubMed: 37279066
DOI: 10.1172/jci.insight.167704 -
Journal of Veterinary Internal Medicine Jul 2021Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing...
BACKGROUND
Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing protocols can be cost-prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive.
OBJECTIVE
To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA.
ANIMALS
Thirty-seven dogs, including 19 test population dogs and 18 controls.
METHODS
Randomized controlled double-blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low-dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days.
RESULTS
Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016-1.029) as compared to test population dogs (1.033, 1.023-1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs.
CONCLUSIONS AND CLINICAL IMPORTANCE
Low-dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard-dose protocols are more likely to result in biochemical evidence of overtreatment.
Topics: Adrenal Insufficiency; Animals; Desoxycorticosterone; Dog Diseases; Dogs; Mineralocorticoids
PubMed: 34114259
DOI: 10.1111/jvim.16195 -
The Journal of Clinical Endocrinology... Oct 2023There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be...
CONTEXT
There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications.
OBJECTIVE
We aimed to identify early, first-trimester prediction markers for GDM.
METHODS
The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55 randomly selected control and 55 women who developed GDM later.
RESULTS
Pregnant women who developed GDM later during the pregnancy were older and had higher body mass index. The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity, testosterone, cortisone, 21-deoxycortisol; soluble urokinase plasminogen activator receptor, dehydroepiandrosterone sulfate, dihydrotestosterone, cortisol, and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model, we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR).
CONCLUSION
Based on these measurements, we accurately predict the development of later-onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.
Topics: Female; Humans; Pregnancy; Cortisone; Desoxycorticosterone; Diabetes, Gestational; Fructosamine; Hydrocortisone; Pregnancy Trimester, First; Case-Control Studies
PubMed: 37247379
DOI: 10.1210/clinem/dgad301 -
Journal of the American Heart... Jul 2023Background Different T-lymphocyte subsets, including CD1d-dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of...
Background Different T-lymphocyte subsets, including CD1d-dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of identifying key immune cells for its treatment. This study aimed to determine the unknown effects of CD1d-dependent NKT cells on hypertension and vascular injury. Methods and Results Hypertension models were induced in male CD1d knockout (CD1dko), wild-type, and adoptive bone marrow transfer mice by angiotensin II (Ang II) or deoxycorticosterone acetate salt. Blood pressure was measured by the tail-cuff system and radiotelemetry. Vascular injury was assessed by histologic studies or aortic ring assay. Inflammation was detected by flow cytometry, quantitative real-time polymerase chain reaction, or ELISA. Results showed that Ang II infusion significantly reduced CD1d expression and NKT cell numbers in the aorta of mice. CD1dko mice exhibited worsened blood pressure elevation, vascular injury, and inflammatory response induced by Ang II or deoxycorticosterone acetate salt. However, these effects were markedly reversed in wild-type mice treated with NKT cell-specific activator. Adoptive transfer of CD1dko bone marrow cells to wild-type mice also significantly worsened Ang II-induced responses. Mechanistically, CD1dko increased Ang II-induced interleukin-6 production and activated signal transducer and activator of transcription 3 and orphan nuclear receptor γ, subsequently inducing interleukin-17A production. Neutralizing interleukin-17A partially reversed Ang II-induced hypertension and vascular injury in CD1dko mice. In addition, levels of NKT cells were lower in the blood of patients with hypertension (n=57) compared with normotensive individuals (n=87). Conclusions These findings reveal a previously unknown role for CD1d-dependent NKT cells in hypertension and vascular injury, indicating that NKT cell activation could be a promising therapeutic target for hypertension.
Topics: Animals; Male; Mice; Acetates; Desoxycorticosterone; Hypertension; Interleukin-17; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Vascular System Injuries
PubMed: 37382154
DOI: 10.1161/JAHA.122.029179