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Cardiovascular disease has been associated with increased levels of reactive oxygen species (ROS). Recently, we have shown that a critical balance between cytosolic ROS and mitochondrial ROS is crucial in cardiovascular health and that modulation of mitochondrial ROS helps prevent detrimental effects of cytosolic ROS on endothelial cells (EC) in transgenic animals. Here, we report the development of a controlled delivery system for a mitochondria‐targeted antioxidant, JP4‐039, from an electrospun scaffold made of FDA‐approved biocompatible polymeric nanofibers. We demonstrate that the active antioxidant moiety was preserved in released JP4‐039 for over 72 h using electron paramagnetic resonance. We also show that both the initial burst release of the drug within the first 20 min and the ensuing slow and sustained release that occurred over the next 24 h improved tube formation in human coronary artery ECs (HCAEC) in vitro. Taken together, these findings suggest that electrospinning methods can be used to upload mitochondrial antioxidant (JP4‐039) onto a biocompatible nanofibrous PLGA scaffold, and the uploaded drug (JP4‐039) retains nitroxide antioxidant properties upon release from the scaffold, which in turn can reduce mitochondrial ROS and improve EC function in vitro. [ABSTRACT FROM AUTHOR]

Background To characterize the health status of selected garment and textile factory workers in Bangladesh using a workplace mobile health clinic. Methods A retrospective review of de-identified worker health information was performed using 1906 medical records. Results The mean age of the workers was 27.9±7.3 y, with 60.3% (1150/1906) female and 39.7% (756/1906) male workers. The most common medical conditions identified were anemia (19.0%; 362/1906), elevated BP (EBP) (11.9%; 226/1906) and elevated fasting blood glucose (FBG) (8.0%; 151/1906). Among the workers who had EBP, 86.3% (195/226) were previously undiagnosed, while out of the workers with elevated FBG, 72.8% (110/151) were newly diagnosed. Men were more likely than women to have EBP (OR 3.5, 95% CI [2.12–5.56], p<0.001), a family history of diabetes (OR 3.6, 95% CI [2.1–5.9], p<0.001) and no formal education (OR 4.9, 95% CI [3.6–6.7], p<0.001). Conclusions Despite the relatively young mean age, significant percentages of workers were identified as having undiagnosed chronic health conditions, including EBP and elevated FBG, that require urgent medical attention and health education. The findings suggest that provision for annual health screening, either by mobile on-site clinics or by training the existing in-house paramedics, will help improve health of the factory workers. [ABSTRACT FROM AUTHOR]

Receptor-mediated signaling is commonly associated with multiple functions, including the production of reactive oxygen species. However, whether mitochondrion-derived superoxide (mROS) contributes directly to physiological signaling is controversial. Here we demonstrate a previously unknown mechanism in which physiologic Ca2+-evoked mROS production plays a pivotal role in endothelial cell (EC) activation and leukocyte firm adhesion. G protein-coupled receptor (GPCR) and tyrosine kinase-mediated inositol 1,4,5-trisphosphate-dependent mitochondrial Ca2+ uptake resulted in NADPH oxidase-independent mROS production. However, GPCR-linked mROS production did not alter mitochondrial function or trigger cell death but rather contributed to activation of NF-κB and leukocyte adhesion via the EC induction of intercellular adhesion molecule 1. Dismutation of mROS by manganese superoxide dismutase overexpression and a cell-permeative superoxide dismutase mimetic ablated NF-κB transcriptional activity and facilitated leukocyte detachment from the endothelium under simulated circulation following GPCR- but not cytokine-induced activation. These results demonstrate that mROS is the downstream effector molecule that translates receptor-mediated Ca2+ signals into proinflammatory signaling and leukocyte/EC firm adhesion. [ABSTRACT FROM AUTHOR]

The promise of injection of extracellular matrix (ECM) from animal hearts as a treatment of myocardial ischemia has been limited by immune reactions and harsh ECM-damaging extraction procedures. We developed a novel method to produce lab-grown human three-dimensional (3-D) acellular ECM particles from human mesenchymal stem cells (MSCs) to mitigate product variability, immunogenicity, and preserve ECM architecture. We hypothesized that intramyocardial injection (I/M) of this novel ECM (dia ∼ 200 microns) would improve cardiac function in a postmyocardial infarction (MI) murine model. WT mice aged 8-10 wk underwent ligation of the left anterior descending coronary (LAD) artery and I/M injection of 10 μL ECM or normal saline ( n = 10/group). Compared with control, ECM-treated hearts showed significant reduction in infarct size ( P = 0.04), increased capillary density in ischemic myocardium ( P = 0.01), and increased fractional shortening (FS) ( P < 0.05) on postoperative days (POD) 14 , 21 , and 28 by echocardiography. There were no significant differences in immunogenic response as determined by TNFα, IL6, CD86, or CD163 levels ( P > 0.05 for all) in the hearts. Biodistribution of fluorophore-conjugated ECM demonstrated localized epifluorescence in the heart after I/M injection, without significant peripheral end organ epifluorescence. Proteomic analysis of ischemic and perfused myocardium from control and ECM-treated hearts using LC-MS/MS ( n = 3/group) detected significant changes in proteins involved in cardiomyocyte contractility and fatty acid metabolism. These findings suggest that 3-D ECM particles induce recovery of ischemic myocardium, by upregulating protein networks involved in cellular contractility and metabolism. Taken together, 3-D ECM particles represent a promising therapy for MI and warrant confirmatory studies in a high-fidelity large animal model. NEW & NOTEWORTHY Our novel lab-grown, human 3-D extracellular matrix (ECM) represents a novel therapeutic approach to prevent pathological remodeling and heart failure in an animal model of heart attack. This novel finding may help develop nonsurgical therapeutic modalities aimed at reducing the global burden of cardiovascular disease.

Objective: Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking., Approach and Results: Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014)., Conclusion: This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.

Aim: Recent studies demonstrate that sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i), two classes of antidiabetic drugs, are cardioprotective. However, the mechanisms of these benefits and their comparative efficacy remain unclear. We aimed to compare the effects of these antidiabetic agents on cardiac function, perfusion, and microvascular density using a swine model of chronic myocardial ischemia., Methods: Chronic myocardial ischemia was induced in Yorkshire swine by ameroid constrictor placement to the left circumflex artery. Two weeks later, pigs were administered vehicle ("CON", 8 pigs), 300 mg SGLT2i canagliflozin, ("CANA", 8 pigs), or 100 mg DPP4i sitagliptin ("SIT", 5 pigs) daily. Five weeks later, pigs were euthanized. Cardiac function, perfusion, collateralization, and protein expression were determined by pressure-volume catheter, microsphere analysis, immunofluorescence, and immunoblotting, respectively., Results: Compared with SIT, CANA was associated with improved stroke volume and cardiac output, with a trend towards reduced left ventricular stiffness. Both CANA and SIT trended towards improved perfusion compared to CON, but there were no differences between the two treatment groups. SIT was associated with improved capillary density with a trend towards improved arteriolar density compared to CANA. Both CANA and SIT were associated with increased expression of vascular endothelial cadherin compared to CON, without differences in treatment groups. SIT pigs had decreased 5' adenosine monophosphate-activated protein kinase activation compared to CON and CANA. There was a trend towards increased endothelial nitric oxide synthase activation in the SIT group compared to CON. There were no differences in activation of extracellular signal-regulated kinase 1/2 across groups., Conclusions: In the setting of chronic myocardial ischemia, canagliflozin is associated with improved cardiac function compared to sitagliptin, with similar effects on perfusion despite differences in microvascular collateralization., Competing Interests: DECLARATIONS Conflicts of interest All authors declared that there are no conflicts of interest.

Microvascular disease plays critical roles in the dysfunction of all organ systems, and there are many methods available to assess the microvasculature. These methods can either assess the target organ directly or assess an easily accessible organ such as the skin or retina so that inferences can be extrapolated to the other systems and/or related diseases. Despite the abundance of exploratory research on some of these modalities and their possible applications, there is a general lack of clinical use. This deficiency is likely due to two main reasons: the need for standardization of protocols to establish a role in clinical practice or the lack of therapies targeted toward microvascular dysfunction. Also, there remain some questions to be answered about the coronary microvasculature, as it is complex, heterogeneous, and difficult to visualize in vivo even with advanced imaging technology. This review will discuss novel approaches that are being used to assess microvasculature health in several key organ systems, and evaluate their clinical utility and scope for further development.

Coronary microvascular disease (CMD), which affects the arterioles and capillary endothelium that regulate myocardial perfusion, is an increasingly recognized source of morbidity and mortality, particularly in the setting of metabolic syndrome. The coronary endothelium plays a pivotal role in maintaining homeostasis, though factors such as diabetes, hypertension, hyperlipidemia, and obesity can contribute to endothelial injury and consequently arteriolar vasomotor dysfunction. These disturbances in the coronary microvasculature clinically manifest as diminished coronary flow reserve, which is a known independent risk factor for cardiac death, even in the absence of macrovascular atherosclerotic disease. Therefore, a growing body of literature has examined the molecular mechanisms by which coronary microvascular injury occurs at the level of the endothelium and the consequences on arteriolar vasomotor responses. This review will begin with an overview of normal coronary microvascular physiology, modalities of measuring coronary microvascular function, and clinical implications of CMD. These introductory topics will be followed by a discussion of recent advances in the understanding of the mechanisms by which inflammation, oxidative stress, insulin resistance, hyperlipidemia, hypertension, shear stress, endothelial cell senescence, and tissue ischemia dysregulate coronary endothelial homeostasis and arteriolar vasomotor function.

Yorkshire swine were fed standard diet ( n = 7) or standard diet containing applesauce rich in caffeic acid with Lactobacillus plantarum ( n = 7) for 3 wk. An ameroid constrictor was next placed around the left coronary circumflex artery, and the dietary regimens were continued. At 14 wk, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated. The L. plantarum -applesauce augmented NF-E2-related factor 2 (Nrf2) in the ischemic myocardium and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the L. plantarum -applesauce supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, whereas levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral-dependent myocardial perfusion was unaffected, whereas arteriolar and capillary densities were reduced as determined by α-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with L. plantarum -applesauce is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density, and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function. NEW & NOTEWORTHY Colonization of the gut microbiome with certain strains of L. Plantarum has been shown to convert caffeic acid readily available in applesauce to 4-vinyl-catechol, a potent activator of the Nrf2 antioxidant defense pathway. In this exciting study, we show that simple dietary supplementation with L. Plantarum -applesauce-mediated Nrf2 activation supports vascular function, ameliorates myocardial ischemic diastolic dysfunction, and upregulates expression of eNOS.

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease, or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell-derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery. However, recent revolutionary developments and insight into the potential of personalizing EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.

Background: Drug repositioning is a key component of COVID-19 pandemic response, through identification of existing drugs that can effectively disrupt COVID-19 disease processes, contributing valuable insights into disease pathways. Traditional non in silico drug repositioning approaches take substantial time and cost to discover effect and, crucially, to validate repositioned effects., Methods: Using a novel in-silico quasi-quantum molecular simulation platform that analyzes energies and electron densities of both target proteins and candidate interruption compounds on High Performance Computing (HPC), we identified a list of FDA-approved compounds with potential to interrupt specific SARS-CoV-2 proteins. Subsequently we used 1.5M patient records from the National COVID Cohort Collaborative to create matched cohorts to refine our in-silico hits to those candidates that show statistically significant clinical effect., Results: We identified four drugs, Metformin, Triamcinolone, Amoxicillin and Hydrochlorothiazide, that were associated with reduced mortality by 27%, 26%, 26%, and 23%, respectively, in COVID-19 patients., Conclusions: Together, these findings provide support to our hypothesis that in-silico simulation of active compounds against SARS-CoV-2 proteins followed by statistical analysis of electronic health data results in effective therapeutics identification., Competing Interests: CONFLICTS OF INTEREST Joy Alamgir is founder of ARIScience. Melissa Haendel is a co-founder of Pryzm Health.

There exist two opposing perspectives regarding reactive oxygen species (ROS) and their roles in angiogenesis and cardiovascular system, one that favors harmful and causal effects of ROS, while the other supports beneficial effects. Recent studies have shown that interaction between ROS in different sub-cellular compartments plays a crucial role in determining the outcomes (beneficial vs. deleterious) of ROS exposures on the vascular system. Oxidant radicals in one cellular organelle can affect the ROS content and function in other sub-cellular compartments in endothelial cells (ECs). In this review, we will focus on a critical fact that the effects or the final phenotypic outcome of ROS exposure to EC are tissue- or organ-specific, and depend on the spatial (subcellular localization) and temporal (duration of ROS exposure) modulation of ROS levels., Competing Interests: The authors declare no conflicts of interest.

Perioperative glucose control is highly important, particularly for patients undergoing cardiac surgery. Variable glucose levels before, during and after cardiac surgery lead to increased post-operative complications and patient mortality. [1] Current methods for intensive monitoring and treating hyperglycemia in the Intensive Care Unit (ICU) usually involve hourly glucose monitoring and continuous intravenous insulin infusions. With the advent of more accurate subcutaneous glucose monitoring systems, the role of improved glucose control with newer systems deserves consideration for widespread adoption.

Sepsis is known as the presence of a Systemic Inflammatory Response Syndrome (SIRS) in response to an infection. In the USA alone, 750,000 cases of severe sepsis are diagnosed annually. More than 70% of sepsis-related deaths occur due to organ failure and more than 50% of septic patients demonstrate cardiac dysfunction. Patients with sepsis who develop cardiac dysfunction have significantly higher mortality, and thus cardiac dysfunction serves as a predictor of survival in sepsis. We have very little understanding about the mechanisms that result in cardiac dysfunction in the setting of sepsis. At present, the factors involved in sepsis-related cardiac dysfunction are believed to include the following: persistent inflammatory changes in the vascular endothelium and endocardium leading to circulatory and micro vascular changes, increase in endothelial reactive oxygen species (ROS), abnormal endothelium-leukocyte interaction resulting in a feed-forward loop for inflammatory cytokines and ROS, contractile dysfunction of the heart due to autonomic dysregulation, metabolic changes in myocardium leading to impaired oxygen delivery and increased oxygen consumption, mitochondrial dysfunction, and persistent inflammatory signaling. In this review article, we will briefly discuss the clinical challenges and our current understanding of cardiac dysfunction in sepsis. Major focus will be on the pathological changes that occur in vascular endothelium, with an emphasis on endocardium, and how endothelial ROS, impaired endothelium-leukocyte interaction, and microcirculatory changes lead to cardiac dysfunction in sepsis. The importance of the ongoing quest for the clinical biomarkers for cardiac dysfunction will also be discussed.

Calpains are a 15-member class of calcium activated nonlysosomal neutral proteases which are involved in a broad range of cellular function. Calpains are usually localized to the cytosol and within mitochondria. Calpastatin is an endogenous protein that specifically binds to and inhibits calpain. Overactivation of calpain has been implicated in a number of disease processes of the brain, eyes, heart, lungs, pancreas, kidneys, vascular system and skeletal muscle. Therefore, calpain may serve as a potential therapeutic target for a wide variety of disease processes. This review briefly outlines the current literature regarding the involvement of calpain overactivation in the pathogenesis of almost every organ in the body.

General use and popularity of over-the-counter supplemental antioxidants have rapidly spread all over the world and are believed to promote cardiovascular health and wellbeing. However, there is a paucity of information and lack of proof that physiological and above-physiological levels of oxidants do harm at the cellular and organismal levels. Instead, several reports demonstrated that reduction in Reactive Oxygen Species (ROS) did not improve vascular function. Interestingly, recent studies show that increased ROS levels play protective role in vascular endothelium and may improve coronary endothelial function. In the current review, we introduce the concept that increased ROS levels, often seen in association with cardiovascular disease, probably is an endothelial-way or 'oxidative response' to cope with vascular pathology.

Receptor-mediated signaling is commonly associated with multiple functions, including the production of reactive oxygen species. However, whether mitochondrion-derived superoxide (mROS) contributes directly to physiological signaling is controversial. Here we demonstrate a previously unknown mechanism in which physiologic Ca(2+)-evoked mROS production plays a pivotal role in endothelial cell (EC) activation and leukocyte firm adhesion. G protein-coupled receptor (GPCR) and tyrosine kinase-mediated inositol 1,4,5-trisphosphate-dependent mitochondrial Ca(2+) uptake resulted in NADPH oxidase-independent mROS production. However, GPCR-linked mROS production did not alter mitochondrial function or trigger cell death but rather contributed to activation of NF-kappaB and leukocyte adhesion via the EC induction of intercellular adhesion molecule 1. Dismutation of mROS by manganese superoxide dismutase overexpression and a cell-permeative superoxide dismutase mimetic ablated NF-kappaB transcriptional activity and facilitated leukocyte detachment from the endothelium under simulated circulation following GPCR- but not cytokine-induced activation. These results demonstrate that mROS is the downstream effector molecule that translates receptor-mediated Ca(2+) signals into proinflammatory signaling and leukocyte/EC firm adhesion.

Despite recent progress in identifying a number of important factors that may play central roles in various renal diseases, the precise molecular basis of renal injuries remains unclear. Recent studies have documented an important role for oxidant stress in several renal diseases. Oxidant stress by overproduction of reactive oxygen species, generation of reactive nitrogen species, and/or modulation of cellular antioxidant enzyme activities, resulting in the activation of certain transcription factors, and synthesis and/or release of inflammatory cytokines, chemokines, growth factors, and extracellular matrix proteins. These changes alter the balance in the microenvironment of the kidney, and may activate signaling cascades that induce and propagate renal injury. Complex molecular interactions and cross-talk between the activated signaling pathways, in turn, define the nature and clinical course of the disease process. In this article, we will briefly present the relevance of the oxidant stress in the pathogenesis of various renal diseases.

Cisplatin (cis-diamminedichloroplatinum(II)) is an effective chemotherapeutic agent, and is successfully used in the treatment of a wide range of tumors. Despite its effectiveness as an anti-tumor drug, nephrotoxic side effects have significantly restricted its clinical use. Tubular epithelial cell deletion following cisplatin treatment is a major cause of renal injury. Oxidative stress significantly contributes to cisplatin-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of cisplatin. The renal microenvironmental changes following cisplatin treatment is a complex process and could be broadly categorized into three main pathological events, which at times might overlap: initial cytotoxic events, inflammatory events and fibroproliferative events. Stress responses and heat shock proteins generated following cisplatin treatment are actively involved in the initiation and progression of these events. In this article, we will briefly summarize factors involved in various phases of cisplatin-induced renal injuries.