Pathogenesis Of Cardiovascular Disease Research Articles

Integrative Bioinformatics Approaches to Uncover Hub Genes and Pathways Involved in Cardiovascular Diseases.

Cardiovascular diseases (CVD) represent a significant global health challenge resulting from a complex interplay of genetic, environmental, and lifestyle factors. However, the molecular pathways and genetic factors involved in the onset and progression of CVDs remain incompletely understood. Here, we performed an integrative bioinformatic analysis to highlight specific genes and signaling pathways implicated in the pathogenesis of 80 CVDs. Differentially expressed genes (DEGs) were identified through the integrated analysis of microarray and GWAS datasets. Then, hub genes were identified after gene ontology functional annotation analysis and protein-protein internet (PPI) analysis. In addition, pathways were identified through KEGG and gene ontology enrichment analyses. A total of 821 hub genes related to 80 CVDs were identified, including 135 common and frequent CVD-associated genes. TNF, IL6, VEGFA, and TGFB.1 genes were the central core genes expressed in 50% or more of CVDs, confirming that the inflammation is a key pathological feature of CVDs. Analysis of hub genes by KEGG enrichment revealed predominant enrichment in 201 KEGG pathways, of which the AGE-RAGE signaling pathway in diabetic complications was identified as the common key KEGG implicated in 62 CVDs. In addition, the outcomes showed an overrepresentation in pathways categorized under human diseases, particularly in the subcategories of infectious diseases and cancers, which may be common risk factors for CVDs. In conclusion, this powerful approach for in silico fine-mapping of genes and pathways allowed the identification of determinant hubs genes and pathways implicated in the pathogenesis of CVDs which could be employed in developing more targeted and effective interventions for preventing, diagnosing, and treating CVDs. The function of these hub genes in CVDs needs further exploration to elucidate their biological characteristics.

HIV-Associated Cardiovascular Disease Pathogenesis: An Emerging Understanding Through Imaging and Immunology.

Cardiac abnormalities were identified early in the epidemic of AIDS, predating the isolation and characterization of the etiologic agent, HIV. Several decades later, the causation and pathogenesis of cardiovascular disease (CVD) linked to HIV infection continue to be the focus of intense speculation. Before the widespread use of antiretroviral therapy, HIV-associated CVD was primarily characterized by HIV-associated cardiomyopathy linked to profound immunodeficiency. With increasing antiretroviral therapy use, viral load suppression, and establishment of immune competency, the effects of HIV on the cardiovascular system are more subtle. Yet, people living with HIV still face an increased incidence of cardiovascular pathology. Advances in cardiac imaging modalities and immunology have deepened our understanding of the pathogenesis of HIV-associated CVD. This review provides an overview of the pathogenesis of HIV-associated CVD integrating data from imaging and immunologic studies with particular relevance to the HIV population originating from high-endemic regions, such as sub-Saharan Africa. The review highlights key evidence gaps in the field and suggests future directions for research to better understand the complex HIV-CVD interactions.

Poly (ADP-ribose) Polymerase-1 modulations in the genesis of thrombosis.

Thrombosis, a coagulation disorder, occurs due to altered levels of coagulation, fibrinolytic and immune factors, which are otherwise known to maintain hemostasis in normal physiological conditions. Here, we review the direct and indirect participation of a multifunctional nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP1) in the expression of key genes and cellular processes involved in thrombotic pathogenesis. PARP1 biological activities range from maintenance of genomic integrity, chromatin remodeling, base excision DNA repair, stress responses to cell death, angiogenesis and cell cycle pathways. However, under homeostatic imbalances, PARP1 activities are linked with the pathogenesis of diseases, including cancer, aging, neurological disorders, and cardiovascular diseases. Disease-associated distressed cells employ a variety of PARP-1 functions such as oxidative damage exacerbations, cellular energetics and apoptosis pathways, regulation of inflammatory mediators, promotion of endothelial dysfunction, and ERK-mediated signaling in pathogenesis. Thrombosis is one such pathogenesis that comprises exacerbation of coagulation cascade due to biochemical alterations in endothelial cells, platelet activation, overexpression of adhesion molecules, cytokines release, and leukocyte adherence. Thus, the activation of endothelial and inflammatory cells in thrombosis implicates a potential role of PARP1 activation in thrombogenesis. This review article explores the direct impact of PARP1 activation in the etiology of thrombosis and discusses PARP1-mediated endothelial dysfunction, inflammation, and epigenetic regulations in the disease manifestation. Understanding PARP1 functions associated with thrombosis may elucidate novel pathogenetic mechanisms and help in better disease management through newer therapeutic interventions targeting PARP1 activity.

#1984 Extracellular vesicles drive loss of endothelial homeostasis in pediatric chronic kidney disease

Abstract Background and Aims Cardiovascular disease (CVD) is the main cause of mortality in chronic kidney disease (CKD). However, the pathogenesis of CVD in CKD remains incompletely understood. Extracellular vesicles (EVs) emerged as mediators of inter-organ cross-talk and endothelial EVs (EC-EVs) were previously associated with CVD. We hypothesized that CKD drives endothelial EV release in CKD and that these EC-EVs drive CVD in CKD. Method A cohort of 94 children (mean age 10.9 years) at different stages of CKD (patients with or without dialysis and after kidney transplantation (KTx)) and age-matched healthy donors was recruited, offering the unique opportunity to analyze cardiovascular effects of CKD and EV dynamics in absence of age-related comorbidities. Thorough characterization of plasma EVs by electron microscopy, nanoparticle tracking analysis (NTA), flow cytometry and miRNA sequencing was carried out. Functional properties of patient EVs and CKD-specific EV release mechanisms were tested in vitro. Results EC-EVs were elevated in hemodialysis (HD) patients (as measured by flow cytometry) while total EV counts showed higher concentrations in peritoneal dialysis patients (according to NTA). Longitudinal follow-ups revealed that EC-EVs decreased after receiving KTx. EV small RNA sequencing showed lower abundance of 30 microRNAs in EVs from CKD patients, most pronounced in HD patients compared to both healthy donors and KTx recipients. Downregulation of let-7d-5p, miR-19a-3p, miR-24-3p, miR-103a-3p and miR-142-3p was confirmed using RT-qPCR. Gene enrichment analyses predicted angiogenesis and smooth muscle cell (SMC) proliferation as targets of differentially regulated miRNAs in CKD. In vitro, angiogenesis of Human Umbilical Vein Endothelial Cells (HUVECs) was decreased upon treatment with CKD EVs as indicated by decreased vascular tube formation, endothelial migration and proliferation while SMC proliferation remained unchanged. To assess the putative role of uremic toxins for EV release in CKD, we focused on tryptophan metabolites and performed targeted plasma metabolomics that showed stage-dependent increases of uremic toxins of indole and kynurenine pathways in children with CKD, with highest levels in dialysis patients and almost normal levels after KTx. Uremic toxins indoxyl sulfate, formylkynurenine and xanthurenic acid correlated positively with EC-EVs in our cohort, but were not sufficient to trigger EV release from aortic endothelial cells alone. However, high shear stress together with indoxyl sulfate increased EV release from venous endothelial cells corresponding to higher endothelial EV concentrations in HD patients with arterio-venous fistulas (AVF) and recapitulated EV miRNA changes in vitro observed in CKD in vivo (lower abundance of let-7d-5p and miR-24-3p). Conclusion Endothelial EV release and decreased EV miRNAs associate with advanced CKD while increased endothelial shear stress and indoxyl sulfate form potential causative factors of altered EV phenotype. CKD EVs inhibit angiogenesis in vitro, potentially caused by dysregulated EV miRNAs that could form novel therapeutical targets to reduce CVD burden in CKD.

#3095 Pinpointing specific circulating microRNAs as putative biomarkers for chronic kidney disease and cardiovascular outcomes

Abstract Background and Aims Chronic kidney disease (CKD) affects over 10% of the worldwide population and entails a significant risk for cardiovascular disease (CVD), leading to an up to 500-fold increase in cardiovascular mortality in advanced stages. However, the pathophysiological mechanisms underlying kidney-heart intercommunication remain unknown. In recent years, microRNAs (miRNAs) emerged as critical regulators of gene expression and numerous miRNAs that have been implicated in both CKD and CVD pathogenesis. Still, so far, their role in kidney-heart crosstalk has not been addressed. In this study, we evaluated the expression of a panel of miRNAs in plasma from pre-dialysis CKD patients and explored their association with main comorbidities and significant outcomes in a 5-year follow up. Method The expression levels of miR-30c-5p, miR-132-3p, miR-199a-5p, and miR-324-3p was assessed by real time qRT-PCR in plasma samples from two cohorts of pre-dialysis CKD patients followed up at the Nephrology Department of Centro Hospitalar Universitário de São João (CHSJ, Porto, Portugal).The discovery cohort was established between November 2014 and August 2018 and comprises 52 CKD patients while the validation cohort comprises samples from 43 CKD patients who underwent a kidney biopsy for diagnostic purposes from November 2019 to December 2022. Patients with acute kidney injury, neoplasia diagnosis, recent infections (<1 week), or known psychiatric disorders were excluded from the study. Plasma samples from 38 healthy blood donors, recruited at the Immunohemotherapy Department of CHSJ, in which creatinine values were measured and considered normal were used as controls. Participants with a history of cancer, inflammatory, or infectious diseases and who were being treated with anti-inflammatory or anti-depressive drugs, were excluded. MiRs expression in comparison with the controls was validated in both cohorts and its expression in the Discovery cohort was correlated with the patients clinical data in a 5 year follow up. Results Results show that miR-30c-5p and miR-132-3p were downregulated in CKD patients compared with healthy controls, presenting a significant power to discriminate the disease condition. Still, considering the stratification of CKD in early/moderate (1-3) and advanced stages (4-5), only miR-30c-5p presented a decreased expression in the initial stages of the disease, showing a significant diagnostic value as an early biomarker for CKD, independently of eGFR. When analyzing the major disease outcomes in a 5 year time, miR-199a-5p was associated with increased frequency of CVD and mortality while miR-324-3p was downregulated in CKD patients that progressed to worse stages. Conclusion These findings highlight miR-30c-5p as a potential biomarker for the diagnosis of CKD in early stages of the disease and identify, for the first time, the enrollment of miR-199a-5p and miR-324-3p in kidney-heart pathophysiological crosstalk, paving the way for the putative establishment of new biomarkers and therapeutic targets for CKD and its outcomes.

Impact of Switching from Cigarette Smoking to Tobacco Heating System Use on Biomarkers of Potential Harm in a Randomized Trial

Smoking cessation reduces the risk of developing smoking-related diseases. Although smoking prevalence has declined, many continue smoking cigarettes. Switching completely to smoke-free alternatives like the Tobacco Heating System (THS) 2.2—a heated tobacco product for which there is evidence demonstrating significantly reduced formation and exposure to harmful chemicals compared to cigarettes—has the potential to reduce the harm caused by continuing to smoke cigarettes. We conducted a 6-month clinical study (NCT02396381) with a 6-month extension (NCT02649556), initially randomizing 984 adult smokers to continue smoking or switch to THS (non-mentholated), of which 672 continued into the extension study. Endpoints were evaluated at baseline and at 3, 6, and 12 months. We longitudinally assessed biomarkers of potential harm (BoPHs) known to be reversible upon smoking cessation as indicators of pathways involved in the pathogenesis of cardiovascular or respiratory diseases and carcinogenicity. The need to cough and safety profile were also assessed. Impact on eight key BoPHs was used as a proxy to evaluate harm reduction potential. At 12 months, comparison of BoPH levels between the predominant THS use and cigarette smoking groups showed a positive effect in favor of switching, partially or in full, to THS. These results provide additional evidence of the harm reduction potential of THS for smokers who would otherwise continue smoking, but they need to be verified in long-term confirmatory studies.

Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease.

Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.

Empagliflozin, a sodium-glucose cotransporter inhibitor enhancing mitochondrial action and cardioprotection in metabolic syndrome.

Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.

Relation Between Exposure to Tobacco Smoke Assessed by Serum Cotinine Concentration and Questionnaire Method, and Serum Renalase Concentration-the Importance of the Coexistence of Arterial Hypertension and Other Cardiovascular Diseases.

Exposure to tobacco smoke (ETS) is one of the main risk factors for cardiovascular disease (CVD). Renalase is a protein that may play a role in the pathogenesis of CVD. The aim of the study was to assess the relationship between ETS and serum renalase concentration. A group of 109 patients was recruited for this study (49.7 ± 14.7years). In accordance with the questionnaire, patients were divided into the following subgroups: subgroup A- declaring themselves active smokers (n = 36), subgroup B- declaring themselves non-smokers and exposed to environmental tobacco smoke (n = 35), subgroup C- declaring themselves non-smokers and not exposed to environmental tobacco smoke (n = 38). The same patients were divided based on cotinine concentration into the following subgroups: subgroup D- active smokers (n = 42), subgroup E- non-smokers exposed to environmental tobacco smoke (n = 66), and subgroup F- non-smokers not exposed to environmental tobacco smoke (n = 1). Serum cotinine concentration and serum renalase concentration were measured using ELISA tests. Serum renalase concentration was statistically significantly higher in subgroup C than in subgroups A and B and in subgroup E and F than in D. There was a negative correlation between serum cotinine concentration and serum renalase concentration (r = -0.41, p < 0.05). Regression analysis showed that higher BMI, higher diastolic blood pressure, coronary artery disease and higher serum cotinine concentration are independent risk factors of lower serum renalase concentration. The questionnaire method of assessing exposure to tobacco smoke was characterized by high sensitivity, but only moderate specificity, especially in terms of assessing environmental exposure to tobacco smoke. In summary, the study showed an independent relationship between exposure to tobacco smoke and lower serum renalase concentration.

Mitochondrial dynamics and the significance of its disturbances in the development of childhood diseases. Part II. Cardiological and endocrinological aspects

In recent years, the dynamics of mitochondrial transformations in cells have been of more concern to both representatives of basic science and researchers in the field of applied medicine. A growing number of observations demonstrate the important regulatory influence of mitochondrial dynamics on a variety of physiological and pathological processes in many, if not all, organ and tissue structures. The prospects for studying the features and regulators of these processes for understanding the pathogenesis of diseases, developing their new biomarkers, as well as treatment technologies seem increasingly significant. The purpose of this article is to review the facts obtained regarding mitochondrial dynamics, which, from the authors’ point of view, deserve the attention of pediatricians. The volume of relevant information turned out to be too extensive to fit into one article, which forced it to be divided into several successive publications. The second part provides information about the role of mitochondrial dynamics disturbances in the pathogenesis of cardiovascular and endocrine diseases in children.

Causal role of circulating inflammatory cytokines in cardiac diseases, structure and function

BackgroundInflammation is implicated in cardiovascular disease (CVD) pathogenesis, but causal roles of specific circulating inflammatory cytokines remain unclear. Mendelian randomization (MR) studies are well-poised to provide etiological insights beyond constraints of conventional research. MethodsWe conducted a large-scale MR study to investigate potential causal relationships of 91 inflammatory proteins with CVD outcomes and cardiac remodeling using summary-level genetic data. Outcomes included coronary artery disease, myocardial infarction, stroke, atrial fibrillation, heart failure, abdominal aortic aneurysm, deep vein thrombosis of lower extremities, pulmonary embolism, cardiac structure and functional parameters. Inverse-variance weighted analysis was undertaken as the primary analysis, with several sensitivity analyses applied. ResultsHepatocyte growth factor (HGF) demonstrated a causal relationship with increased susceptibility to both any stroke (OR 1.111; 95 % CI 1.044 - 1.183; P = 9.50e-04) and ischemic stroke (OR 1.121; 95 % CI 1.047 - 1.200; P = 1.04e-03). Programmed cell death 1 ligand 1 (PD-L1) was negatively associated with atrial fibrillation risk (OR 0.936, 95 % CI 0.901 - 0.973; P = 7.69e-04). CCL20, CDCP1, Flt3L and IL-10RA were identified as causal coronary artery disease risk factors, while LIF and ST1A1 had protective effects. IL-4 and LIF-R demonstrated causal links with right heart functional changes. ConclusionsOur MR study nominates specific circulating inflammatory cytokines as potential targets for CVD treatment and prevention. Further research into mechanisms and clinical translation are warranted.

Impact of Inducible Nitric Oxide Synthase Activation on Endothelial Behavior under Magnesium Deficiency.

Endothelial dysfunction is a crucial event in the early pathogenesis of cardiovascular diseases and is linked to magnesium (Mg) deficiency. Indeed, in endothelial cells, low Mg levels promote the acquisition of a pro-inflammatory and pro-atherogenic phenotype. This paper investigates the mechanisms by which Mg deficiency promotes oxidative stress and affects endothelial behavior in human umbilical vascular endothelial cells (HUVECs). Our data show that low Mg levels trigger oxidative stress initially by increasing NAPDH oxidase activity and then by upregulating the pro-oxidant thioredoxin-interacting protein TXNIP. The overproduction of reactive oxygen species (ROS) activates NF-κB, leading to its increased binding to the inducible nitric oxide synthase (iNOS) promoter, with the consequent increase in iNOS expression. The increased levels of nitric oxide (NO) generated by upregulated iNOS contribute to disrupting endothelial cell function by inhibiting growth and increasing permeability. In conclusion, we provide evidence that multiple mechanisms contribute to generate a pro-oxidant state under low-Mg conditions, ultimately affecting endothelial physiology. These data add support to the notion that adequate Mg levels play a significant role in preserving cardiovascular health and may suggest new approaches to prevent or manage cardiovascular diseases.

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases.

Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to the hydroxyl terminus of serine and threonine of proteins. O-GlcNAcylation is responsive to cellular stress as a reversible and posttranslational modification of nuclear, mitochondrial and cytoplasmic proteins. Mitochondrial proteins are the main targets of O-GlcNAcylation and O-GlcNAcylation is a key regulator of mitochondrial homeostasis by directly regulating the mitochondrial proteome or protein activity and function. Disruption of O-GlcNAcylation is closely related to mitochondrial dysfunction. More importantly, the O-GlcNAcylation of cardiac proteins has been proven to be protective or harmful to cardiac function. Mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance of mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs). In this review, we will focus on the interactions between protein O-GlcNAcylation and mitochondrial homeostasis and provide insights on the role of mitochondrial protein O-GlcNAcylation in CVDs.

FOXO1 regulates RUNX2 ubiquitination through SMURF2 in calcific aortic valve disease

The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.

Association of serum uric acid level with intracranial aneurysms: A Mendelian randomization study

ObjectiveNumerous studies have posited the involvement of serum uric acid (SUA) in the pathogenesis and progression of various cardiovascular diseases, particularly aortic aneurysms. However, the casual effect of SUA level on intracranial aneurysms (IAs) was rarely studied. Consequently, we aimed to explore the causal association between SUA and IAs using Mendelian randomization (MR) analysis. MethodsWe conducted a two-sample MR analysis with SUA as the exposure variable and IAs as the outcome variable. Genome-wide association study (GWAS) datasets for SUA were acquired from the Open GWAS catalog, including 389,404 European and 129,405 East Asian individuals. The dataset for IAs was sourced from a meta-analysis of GWASs comprising 317,636 individuals across different ancestral populations (European: 7,495 cases and 71,934 controls; East Asian: 3,259 cases and 234,948 controls). All MR analyses were performed according to populations (European and East Asian) and IAs status [unruptured IAs (uIAs) or aneurysmal subarachnoid hemorrhage (aSAH)], respectively. The inverse variance weighted (IVW) method was employed as primary analysis to discern causal estimates. ResultsOur findings revealed that an elevated genetically predicted SUA level (mg/dL) correlated with an increased risk of IAs among the European population (OR=1.29 [95%CI:1.05-1.57], P=0.013) and East Asian population (OR=1.56 [95%CI: 1.27-1.92], P<0.001). Among European individuals, subgroup analysis indicated a persistent causal association of SUA with uIAs (OR=1.50 [95%CI: 1.08-2.08], P=0.015) and aSAH (OR=1.26 [95%CI: 1.00-1.60], P=0.049). However, subgroup analysis in East Asian populations was not conducted due to the lack of separate data on uIAs and aSAH. ConclusionsOur MR analysis demonstrated a causal relationship between elevated SUA levels and an amplified risk of IAs. Further rigorous investigations are imperative to provide evidence and elucidate the underlying mechanisms.

Role of neuraminidase in promoting the shedding of endothelial mechanosensing structures in type 2 diabetes

Endothelial dysfunction represents a causal factor in the pathogenesis of cardiovascular disease associated with type 2 diabetes (T2D). Previous work shows that endothelial mechanosensing structures are degraded in T2D, resulting in impaired shear stress mechanotransduction and decreased endothelial-derived nitic oxide (NO) bioavailability. Recent evidence suggests that glypican-1, a well-known mechanosensor, is a substrate of the proinflammatory enzyme a disintegrin and metalloproteinase-17 (ADAM17). A key step in ADAM17 activation is externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane, which can be mediated by the phospholipid scramblase anoctamin-6 (ANO6). However, whether ANO6-mediated activation of ADAM17 leads to glypican-1 shedding in endothelial cells remains unknown. Also unknown are the mechanisms by which this pathway becomes overactive in T2D. We recently reported that T2D is associated with increased circulating levels of neuraminidase, a soluble enzyme that cleaves sialic acid residues. We also showed that intraluminal exposure of isolated arteries to neuraminidase impairs shear stress mechanotransduction. Herein, we tested the hypothesis that neuraminidase-induced impaired shear stress mechanotransduction is mediated by ANO6-induced ADAM17 activation and consequent shedding of glypican-1. All reported differences are significant at P&lt;0.05. In support of our hypothesis, we show that neuraminidase and ADAM17 activities are increased, while nitrite (NO surrogate) is decreased, in plasma of men and women with T2D who also display evidence of impaired shear stress mechanotransduction ( i.e., diminished flow-mediated dilation). In cultured endothelial cells, we show that neuraminidase exposure decreases sialic acid content and increases intracellular Ca2+ mobilization, adhesion of lactadherin (a peptide that binds externalized PS), ADAM17 activity, and shedding of glypican-1. Also in cultured endothelial cells, overexpression of ADAM17 increases shedding of glypican-1 and impairs shear stress-induced activation of endothelial NO synthase. Congruently, intraluminal exposure of human omental arteries to active ADAM17 recombinant protein impairs flow-mediated dilation. Furthermore, silencing of ANO6 reduces ADAM17 activity, leading to increased presence of glypican-1 on the endothelial cell surface. Taken together, we provide evidence that neuraminidase, an enzyme increased in the circulation of individuals with T2D, promotes ANO6-dependent externalization of PS in endothelial cells, which in turn leads to ADAM17 activation and consequent shedding of glypican-1. Thus, this work supports the idea that the neuraminidase-ANO6-ADAM17 axis should be considered as a potential target for restoring endothelial mechanosensation and improving NO bioavailability in T2D. R01HL151384 (to LAML and JP), R01HL153264 (to LAML and JP), R01HL137769 (to JP), and R21DK116081 (to CM-A). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Phosphatidylserine supplementation as a potential strategy to improve endothelial function in type 2 diabetes

Endothelial dysfunction represents a causal factor in the pathogenesis of cardiovascular disease associated with type 2 diabetes (T2D), including hypertension. Previous work has revealed that endothelial mechanosensing structures are degraded in T2D, resulting in impaired shear stress mechanotransduction and decreased flow-mediated dilation (FMD). One well-known mechanosensor that is susceptible to cleavage is glypican-1, a prominent proteoglycan member of the endothelial glycocalyx. In this regard, recent evidence from a proteomic analysis suggests that glypican-1 is a substrate of the proinflammatory enzyme ADAM17 (a disintegrin and metalloproteinase-17), which is elevated in the vasculature of T2D. Recent work has revealed that exogenous phosphatidylserine (PS) inhibits in vitro ADAM17 sheddase activity, which may aid in retaining the membrane-bound glypican-1. Therefore, we hypothesized that oral administration of PS in diabetic mice (db/db) would enhance shear stress mechanotransduction, as assessed by FMD, and that this would be accompanied by greater presence of glypican-1 on the endothelial surface. We further hypothesized that PS would reduce blood pressure. We tested this hypothesis in ~10-week-old db/db male mice that were randomized to receive a daily peanut butter pellet as vehicle control or the pellet mixed with soy-derived PS (200 mg/kg/day) for 28 days. A third group of untreated age-matched wild-type C57BL/6J male mice served as healthy controls. Excised mesenteric arteries were used for assessment of FMD using pressure myography, while femoral arteries were used for determining presence of glypican-1 content on the endothelial surface using confocal microscopy. Blood pressure was assessed using the tail-cuff method. All reported differences are significant at p&lt;0.05. Compared with wild-types, untreated db/db mice had impaired FMD, reduced presence of endothelial glypican-1, and increased blood pressure. Notably, these effects were not observed in db/db mice treated with PS. These findings suggest that oral PS may be effective at improving indices of endothelial dysfunction in T2D, an effect likely mediated by the retention of endothelial mechanosensor glypican-1 via reduced ADAM17 sheddase activity. No support to disclose. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs.

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

Nrf2-Keap1 in Cardiovascular Disease: Which is the Cart and Which the Horse?

High levels of oxidant stress in the form of reactive oxidant species (ROS) are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction.

Applied physiology: gut microbiota and antimicrobial therapy.

The gut microbiota plays an important role in maintaining human health and in the pathogenesis of several diseases. Antibiotics are among the most commonly prescribed drugs and have a significant impact on the structure and function of the gut microbiota. The understanding that a healthy gut microbiota prevents the development of many diseases has also led to its consideration as a potential therapeutic target. At the same time, any factor that alters the gut microbiota becomes important in this approach. Exercise and antibacterial therapy have a direct effect on the microbiota. The review reflects the current state of publications on the mechanisms of intestinal bacterial involvement in the pathogenesis of cardiovascular, metabolic, and neurodegenerative diseases. The physiological mechanisms of the influence of physical activity on the composition of the gut microbiota are considered. The mechanisms of the common interface between exercise and antibacterial therapy will be considered using the example of several socially important diseases. The aim of the study is to show the physiological relationship between the effects of exercise and antibiotics on the gut microbiota.