Cardiovascular Disease Function Research Articles

Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection.

Indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan, has been proven to fulfill an essential function in cardiovascular disease (CVD) and nerve regeneration disease. However, the role of IPA in aortic dissection (AD) has not been revealed. We aimed to investigate the role of IPA in the pathogenesis of AD and the underlying mechanisms of IPA in endothelial dysfunction. Untargeted metabolomics has been employed to screen the plasma metabolic profile of AD patients in comparison with healthy individuals. Network pharmacology provides insights into the potential molecular mechanisms underlying IPA. 3-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang II) were administered to induce AD in mice, while human umbilical vein endothelial cells (HUVECs) were employed for in vitro validation of the signaling pathways predicted by network pharmacology. A total of 224 potentially differential plasma metabolites were identified in the AD patients, with 110 up-regulated metabolites and 114 down-regulated metabolites. IPA was the most significantly decreased metabolite involved in tryptophan metabolism. Bcl2, caspase3, and AKT1 were predicted as the target genes of IPA by network pharmacology and molecular docking. IPA suppressed Ang II-induced apoptosis, intracellular ROS generation, inflammation, and endothelial tight junction (TJ) loss. Animal experiments demonstrated that administration of IPA alleviated the occurrence and severity of AD in mice. Taken together, we identified a previously unexplored association between tryptophan metabolite IPA and AD, providing a novel perspective on the underlying mechanism through which IPA mitigates endothelial dysfunction to protect against AD.

High-Density Lipoprotein Metabolism and Function in Cardiovascular Diseases: What about Aging and Diet Effects?

Cardiovascular diseases (CVDs) have become the leading global cause of mortality, prompting a heightened focus on identifying precise indicators for their assessment and treatment. In this perspective, the plasma levels of HDL have emerged as a pivotal focus, given the demonstrable correlation between plasma levels and cardiovascular events, rendering them a noteworthy biomarker. However, it is crucial to acknowledge that HDLs, while intricate, are not presently a direct therapeutic target, necessitating a more nuanced understanding of their dynamic remodeling throughout their life cycle. HDLs exhibit several anti-atherosclerotic properties that define their functionality. This functionality of HDLs, which is independent of their concentration, may be impaired in certain risk factors for CVD. Moreover, because HDLs are dynamic parameters, in which HDL particles present different atheroprotective properties, it remains difficult to interpret the association between HDL level and CVD risk. Besides the antioxidant and anti-inflammatory activities of HDLs, their capacity to mediate cholesterol efflux, a key metric of HDL functionality, represents the main anti-atherosclerotic property of HDL. In this review, we will discuss the HDL components and HDL structure that may affect their functionality and we will review the mechanism by which HDL mediates cholesterol efflux. We will give a brief examination of the effects of aging and diet on HDL structure and function.

Elevated SLC40A1 impairs cardiac function and exacerbates mitochondrial dysfunction, oxidative stress, and apoptosis in ischemic myocardia.

Iron homeostasis is crucial for optimal cardiac function. Iron deficiency and overload have been linked to the development of cardiomyopathy and heart failure (HF) via intricate mechanisms. Although the crucial role of SLC40A1 in iron metabolism by facilitating the efflux of cellular iron has been confirmed, its specific molecular functions in cardiovascular diseases remain poorly understood. In this study, we generated mice with inducible cardiomyocyte-specific overexpression of SLC40A1 for the first time. The overexpression of SLC40A1 in the cardiomyocytes of adult mice resulted in significant iron deficiency, leading to mitochondrial dysfunction, oxidative stress, and apoptosis, subsequently resulting in the development of fatal HF. Notably, SLC40A1 upregulation was observed in the ischemic region during the initial phase of myocardial infarction (MI), contributing to iron loss in the cardiomyocytes. Conversely, the cardiomyocyte-specific knockdown of SLC40A1 improved cardiac dysfunction after MI by enhancing mitochondrial function, suppressing oxidative stress, and reducing cardiomyocytes apoptosis. Mechanistically, Steap4 interacted with SLC40A1, facilitating SLC40A1-mediated iron efflux from cardiomyocytes. In short, our study presents evidence for the involvement of SLC40A1 in the regulation of myocardial iron levels and the therapeutic benefits of cardiomyocyte-specific knockdown of SLC40A1 in MI in mice.

Abstract 17622: CCN3 Deficiency in Myeloid Cells Exacerbates Aortic Dissection by Governing a Proinflammatory Program in Macrophages

Introduction: Aortic dissection (AD) is a fatal disease. Macrophages are known central regulators of aortic inflammation and elastic fiber disruption, two major hallmarks of AD. Cellular communication network factor 3 (CCN3/NOV) is a matricellular protein associated with various biological cellular functions in cardiovascular disease and cancers. Emerging evidence strongly implicates a protective role of CCN3 against several types of vascular pathologies, however its role in AD remains unknown. Hypothesis: CCN3 deficiency in myeloid cells promotes AD development in murine models through the modulation of macrophage phenotype. Aims: We investigated the causal role of CCN3 loss in AD pathogenesis, focusing on its role in macrophages. Methods: 3-4-week-old male myeloid-specific CCN3 knockout mice (CCN3F/F;LysMCre) and control mice (LysMCre) were given BAPN (β-aminopropionitrile monofumarate; 0.2%) in their drinking water for 4 weeks for AD modeling. Mouse survival rate and histological changes of the aorta were assessed. Single cell RNA sequencing analysis was performed to recapitulate cellular transcriptome profile changes. Finally, gain and loss of function studies in bone marrow-derived macrophages (BMDMs) were performed to decipher the underlying mechanism by which CCN3 controls macrophage plasticity. Results: Following BAPN administration, myeloid-specific CCN3 knockout mice had a higher mortality rate due to AD formation and aortic rupture. In accordance with this phenotype, vascular media thickness was markedly reduced, and elastic fiber fragmentation and macrophage infiltration were elevated in myeloid-specific CCN3 knockout mice. Using single-cell RNA-seq, we found that myeloid-deficiency of CCN3 was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages. Furthermore, CCN3 deficient BMDMs are prone to M1 macrophage polarization, an effect dependent on the activation of the JAK/STAT1 signaling pathway. Conclusions: Myeloid-deficiency of CCN3 drives vascular macrophages toward an M1-like, pathogenic phenotype and promotes dissecting aortic aneurysm.

Non-coding RNAs regulating mitochondrial function in cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of disease-related death worldwide and a significant obstacle to improving patients' health and lives. Mitochondria are core organelles for the maintenance of myocardial tissue homeostasis, and their impairment and dysfunction are considered major contributors to the pathogenesis of various CVDs, such as hypertension, myocardial infarction, and heart failure. However, the exact roles of mitochondrial dysfunction involved in CVD pathogenesis remain not fully understood. Non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RNAs, and circular RNAs, have been shown to be crucial regulators in the initiation and development of CVDs. They can participate in CVD progression by impacting mitochondria and regulating mitochondrial function-related genes and signaling pathways. Some ncRNAs also exhibit great potential as diagnostic and/or prognostic biomarkers as well as therapeutic targets for CVD patients. In this review, we mainly focus on the underlying mechanisms of ncRNAs involved in the regulation of mitochondrial functions and their role in CVD progression. We also highlight their clinical implications as biomarkers for diagnosis and prognosis in CVD treatment. The information reviewed herein could be extremely beneficial to the development of ncRNA-based therapeutic strategies for CVD patients.

Venous endothelial function in cardiovascular disease.

The essential role of the endothelium in vascular homeostasis is associated with the release of endothelium-dependent relaxing and contractile factors (EDRF and EDCF, respectively). Different from arteries, where these factors are widely studied, the vasoactive factors derived from the venous endothelium have been given less attention. There is evidence for a role of the nitric oxide (NO), endothelium-dependent hyperpolarization (EDH) mechanism, and cyclooxygenase (COX)-derived metabolites as EDRFs; while the EDCFs need to be better evaluated since no consensus has been reached about their identity in venous vessels. The imbalance between the synthesis, bioavailability, and/or action of EDRFs and/or EDCFs results in a pathological process known as endothelial dysfunction, which leads to reduced vasodilation and/or increased vasoconstriction. In the venous system, endothelial dysfunction is relevant since reduced venodilation may increase venous tone and decrease venous compliance, thus enhancing mean circulatory filling pressure, which maintains or modify cardiac workload contributing to the etiology of cardiovascular diseases. Interestingly, some alterations in venous function appear at the early stages (or even before) the establishment of these diseases. However, if the venous endothelium dysfunction is involved in these alterations is not yet fully understood and requires further studies. In this sense, the present study aims to review the current knowledge on venous endothelial function and dysfunction, and the general state of the venous tone in two important cardiovascular diseases of high incidence and morbimortality worldwide: hypertension and heart failure.

Unraveling the epitranscriptome of small non-coding RNAs in vascular cells

Unraveling the epitranscriptome of small non-coding RNAs in vascular cells

Meet the First Authors.

HomeCirculation ResearchVol. 131, No. 10Meet the First Authors Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Authors Originally published27 Oct 2022https://doi.org/10.1161/RES.0000000000000580Circulation Research. 2022;131:790–791Sox17 Deficiency Promotes PAH via c-Met Activation (p 792)Download figureDownload PowerPointDr Chan Soon Park is a clinical fellow in the Division of Cardiology at Seoul National University Hospital (SNUH). He earned his BS and MS in Medicine from Seoul National University and his PhD in Medical Science and Engineering from Korea Advanced Institute of Science and Technology (KAIST). During the PhD program in Graduate School of Medical Science and Engineering in KAIST, he was able to learn basic and translational research, the importance of which has been increasingly emphasized in the development of novel and clinically relevant therapeutic strategies in the field of cardiology. Dr Park continues to expand his research in the roles of endothelial cells in various cardiovascular diseases (CVDs) beyond pulmonary arterial hypertension. He also has interests in clinical research, including the association between metabolic profiles and CVDs as well as the role of imaging in CVD risk stratification. Outside of work, he enjoys hiking and spending time with his family.Prohibitin2 Maintains VSMC Contractile Phenotype (p 807)Download figureDownload PowerPointDr Yiting Jia is a postdoctoral fellow at Peking University Health Science Center (PI: Dr Wei Kong and Dr Caihong Yun). He earned his PhD from Peking University. His early experience in research was focused on metabolism reprogramming, lysosome biology and cardiovascular diseases. Now he is gearing up to become an independent research investigator. Outside of work, he enjoys soccer, tennis and listening to music.Download figureDownload PowerPointDr Chenfeng Mao is a research associate at the Beijing Institute of Biotechnology in Beijing, China. He earned a PhD in human physiology from the Department of Physiology and Pathophysiology in Peking University (mentor, Dr Wei Kong). His research focuses on extracellular matrix microenvironment on vascular remodeling during physiological and disease state. Outside of work he enjoys playing badminton.MED1, BMP/TGF-β and Pulmonary Hypertension (p 828)Download figureDownload PowerPointDr Chen Wang earned her PhD from Xi’ an Jiaotong University. During her PhD studies, she was also trained in the laboratory of Dr Ingrid Fleming at the Institute of Vascular Research, Goethe University. Her research focuses on endothelial dysfunction involved in vascular diseases. She was awarded the “Paul Dudley White International Scholar” from ATVB in 2022 and has published several first-author papers including in Circulation and Circulation Research. Her career goal is to become a physician scientist working on cardiovascular diseases and related translational research. Outside of work, she enjoys traveling, music and baking.Download figureDownload PowerPointYuanming Xing is a PhD candidate in internal medicine at Xi’an Jiaotong University. She also studied computational biology at Warshel Institute for Computational Biology at the Chinese University of Hong Kong-Shenzhen. She is interested in endothelial function in cardiovascular diseases and has published several papers in the related fields. Her career plan is to become a physician who is also proficient in computational biology. She enjoys learning new things, especially what she may not be good at. In her spare time, she has a passion for animal rescue, computer programming and painting.Intrapericardial Exosomes Repair Heart via Foxo3 (p e135)Download figureDownload PowerPointDr Dashuai Zhu is a postdoctoral research fellow in the BioTherapeutics Lab, headed by Dr Ke Cheng (UNC Chapel Hill and North Carolina State University). Dashuai earned his PhD from the Nankai University, China, where he started his career on cardiac repair using tissue engineering and biomedical engineering approaches. His research focuses on regenerative medicine approaches for the treatment of heart disease, with a particular interest in cell and cell-free therapies for myocardial infarction and heart failure. He can be found on Twitter @das_zhu.Download figureDownload PowerPointDr Ke Huang is an assistant research professor in the Department of Molecular Biomedical Sciences at North Carolina State University. He earned his MD in 2008 from Shanxi Medical University and PhD from North Carolina State University. His postdoctral training was at Duke University. His research focuses on regenerative medicine strategies with a particular interest in adult stem cells, biomaterials and nanomedicine approaches. He can be found on [email protected] Previous Back to top Next FiguresReferencesRelatedDetails October 28, 2022Vol 131, Issue 10 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000580PMID: 36302055 Originally publishedOctober 27, 2022 PDF download Advertisement SubjectsAgingCardiovascular DiseaseExercise

The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included “mitochondria”, “exercise”, “aerobic capacity”, and “cardiovascular disease” in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I2 = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients.

Natural IgM attenuate formation of neutrophil extracellular traps induced by oxidation-specific epitopes in vitro and in vivo

Abstract Background Neutrophil extracellular traps (NETs) emerged as important drivers of thrombus formation in acute myocardial infarction (AMI). Therefore, mechanistic understanding of inducers and modulators of NETosis at the site of occlusion is pivotal for new diagnostic and therapeutic approaches. Many triggers of NET formation have been described, among them oxidations-specific epitopes (OSE), products of lipid peroxidation. Extracellular vesicles (EV) carrying OSE are elevated in AMI. OSE-EV can be recognized by natural IgM antibodies exerting protective functions in cardiovascular disease by reducing the pro-inflammatory response to OSE. Purpose We hypothesized that EV-induced NET formation could be dampened by OSE-IgM in vitro and in vivo. Methods Patients were recruited after diagnosis of ST-segment elevation myocardial infarction (STEMI, n=51). Blood was aspirated from the culprit site during percutaneous coronary intervention and at several follow-up time points. Myocardial function was assessed by cardiac magnetic resonance (CMR) at 72 hours and 6 months. EV were isolated by ultracentrifugation and characterized by flow cytometry staining for CD45, CD41a, CD144, and OSE. Isolated EV were used for neutrophil stimulation in vitro and in vivo employing a murine injection model. NETs were visualized by immunofluorescence, staining for DNA, histones, citrullinated histone 3, and myeloperoxidase. NET markers and natural IgM recognizing OSE (OSE-IgM) in murine and patient plasma were measured by ELISA. Results EVs of endothelial, leukocyte, and platelet origin revealed a prominent absolute and relative increase of the OSE-carrying population as recognized by the malondialdehyde-specific antibody LR04. Plasma derived from the site of occlusion contained more and proportionally higher levels of OSE-EV derived from CD45+ cells than the intra-patient peripheral control. No difference was observed for EV of platelet origin, and the endothelial-derived subset of OSE-EV was decreased at the culprit site. OSE-EV and NET markers were positively associated in the circulation. Decreasing OSE-IgM levels during hospital stay indicated consumption of protective antibodies. EV isolated from AMI patient plasma were revealed to induce NET formation in neutrophils in vitro and after injection into mice in vivo, as measured by cell-free DNA and fluorescence microscopy of citrullinated histones in neutrophils. The LR04 IgM antibody, but not a control IgM, reduced the NETogenic effect of EV in both models. Consistently, higher circulating levels of EV and lower OSE-IgM were associated with a reduced ejection fraction in AMI patients at 72 hours and six months. Conclusion EV from AMI patients induced NETosis in vitro and in vivo. IgM recognizing malondialdehyde-epitopes diminished this effect indicating that the balance between OSE-EV and OSE-IgM during AMI may represent a potential prognostic and therapeutic target with impact on heart function. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Vienna Science and Technology Fund (WWTF)

The role of immune checkpoints in cardiovascular disease.

Immune checkpoint inhibitors (ICI) are monoclonal antibodies which bind to immune checkpoints (IC) and their ligands to prevent inhibition of T-cell activation by tumor cells. Currently, multiple ICI are approved targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Programmed Death Protein 1 (PD-1) and its ligand PD-L1, and Lymphocyte-activation gene 3 (LAG-3). This therapy has provided potent anti-tumor effects and improved prognosis for many cancer patients. However, due to systemic effects, patients can develop immune related adverse events (irAE), including possible life threatening cardiovascular irAE, like atherosclerosis, myocarditis and cardiomyopathy. Inhibition of vascular IC is associated with increased atherosclerotic burden and plaque instability. IC protect against atherosclerosis by inhibiting T-cell activity and cytokine production, promoting regulatory T-cell differentiation and inducing T-cell exhaustion. In addition, PD-L1 on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart, IC downregulate the immune response to protect against cardiac injury by reducing T-cell activity and migration. Here, inhibition of IC could induce life-threatening T-cell-mediated-myocarditis. One proposed purpose behind lymphocyte infiltration is reaction to cardiac antigens, caused by decreased self-tolerance, and thereby increased autoimmunity because of IC inhibition. In addition, there are several reports of ICI-mediated cardiomyopathy with immunoglobulin G expression on cardiomyocytes, indicating an autoimmune response. IC are mostly known due to their cardiotoxicity. However, t his review compiles current knowledge on mechanisms behind IC function in cardiovascular disease with the aim of providing an overview of possible therapeutic targets in prevention or treatment of cardiovascular irAEs.

Hydrogen Sulfide Regulates Macrophage Function in Cardiovascular Diseases.

Significance: Hydrogen sulfide (H2S) is an endogenous gasotransmitter that plays a vital role in immune system regulation. Recently, the regulation of macrophage function by H2S has been extensively and actively recognized. Recent Advances: The mechanisms by which endogenous H2S controls macrophage function have attracted increasing attention. The generation of endogenous H2S from macrophages is mainly catalyzed by cystathionine-γ-lyase. H2S is involved in the macrophage activation and inflammasome formation, which contributes to macrophage apoptosis, adhesion, chemotaxis, and polarization. In addition, H2S has redox ability and interacts with reactive oxygen species to prevent oxidative stress. Moreover, H2S epigenetically regulates gene expression. Critical Issues: In this article, the generation of endogenous H2S in macrophages and its regulatory effect on macrophage function are reviewed. In addition, the signal transduction targeting macrophages by H2S is also addressed. Finally, the potential therapeutic effect of H2S on macrophages is discussed. Future Directions: Further experiments are required to explore the involvement of endogenous H2S in the regulation of macrophage function in various physiological and pathophysiological processes and elucidate the mechanisms involved. Regarding the clinical translation of H2S, further exploration of the application of H2S in inflammation-related diseases is needed. Antioxid. Redox Signal. 38, 45-56.

Thinking from the heart: arrhythmia-induced reduction in cerebral blood flow and the cumulative burden on cognitive function in cardiovascular disease.

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Rapid quantification of bioactive compounds in Salvia miltiorrhiza Bunge derived decoction pieces, dripping pill, injection, and tablets by polarity-switching UPLC-MS/MS.

Salvia miltiorrhiza Bunge (SMB) has unambiguous biological functions in cardiovascular diseases, thus has been processed into different medicine forms. However, universal analytical method for fast quantification of bioactive compounds in SMB and SMB derived products is still missing. In this study, a polarity switching strategy was developed and optimized, which enabled the detection of the target compound in both positive and negative ion modes in a single run. The MS2 features of each compound were characterized to select the most prominent transitions for quantitative and qualitative analysis. Afterwards, the performance of this method was validated in terms of linearity (≥0.9916), limit of detection (LOD, 0.003–0.135 ngml−1), limit of quantification (LOQ, 0.010–0.450 ngml−1), precision (48.23 ± 2.58 ngml−1 to 53.72 ± 3.11 ngml−1), recovery (RSD 2.04%–5.79%), and stability (RSD ≤7.52%). Finally, the bioactive compounds in SMB and SMB derived products were determined, among which salvianate A, salvianolic acid A, and rosmarinic acid were the main components in all samples. In conclusion, the polarity switching UPLC-MS/MS method is efficient in accurate determining the bioactive compounds, which greatly shorten the time for analysis when compared with conventional methods. It has great potential quality control of SMB and SMB derived products.

Interplay between Zn2+ Homeostasis and Mitochondrial Functions in Cardiovascular Diseases and Heart Ageing.

Zinc plays an important role in cardiomyocytes, where it exists in bound and histochemically reactive labile Zn2+ forms. Although Zn2+ concentration is under tight control through several Zn2+-transporters, its concentration and intracellular distribution may vary during normal cardiac function and pathological conditions, when the protein levels and efficacy of Zn2+ transporters can lead to zinc re-distribution among organelles in cardiomyocytes. Such dysregulation of cellular Zn2+ homeostasis leads to mitochondrial and ER stresses, and interrupts normal ER/mitochondria cross-talk and mitophagy, which subsequently, result in increased ROS production and dysregulated metabolic function. Besides cardiac structural and functional defects, insufficient Zn2+ supply was associated with heart development abnormalities, induction and progression of cardiovascular diseases, resulting in accelerated cardiac ageing. In the present review, we summarize the recently identified connections between cellular and mitochondrial Zn2+ homeostasis, ER stress and mitophagy in heart development, excitation–contraction coupling, heart failure and ischemia/reperfusion injury. Additionally, we discuss the role of Zn2+ in accelerated heart ageing and ageing-associated rise of mitochondrial ROS and cardiomyocyte dysfunction.

Evidence for the Benefits of Melatonin in Cardiovascular Disease.

The pineal gland is a neuroendocrine gland which produces melatonin, a neuroendocrine hormone with critical physiological roles in the circadian rhythm and sleep-wake cycle. Melatonin has been shown to possess anti-oxidant activity and neuroprotective properties. Numerous studies have shown that melatonin has significant functions in cardiovascular disease, and may have anti-aging properties. The ability of melatonin to decrease primary hypertension needs to be more extensively evaluated. Melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species. Moreover, melatonin may also prevent the hypertrophy of the heart muscle under some circumstances, which in turn would lessen the development of heart failure. Several currently used conventional drugs show cardiotoxicity as an adverse effect. Recent rodent studies have shown that melatonin acts as an anti-oxidant and is effective in suppressing heart damage mediated by pharmacologic drugs. Therefore, melatonin has been shown to have cardioprotective activity in multiple animal and human studies. Herein, we summarize the most established benefits of melatonin in the cardiovascular system with a focus on the molecular mechanisms of action.

Differential Expression of Adipokines in Mechanically Stretched‐ Endothelial cells

IntroductionHypertension is considered as the major risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality worldwide. This disease can develop mainly due to the mechanical forces exerted by the blood on the vessels wall. The endothelium, lining the blood vessel, responds to these hemodynamic mechanical forces such as mechanical stretch leading to endothelial dysfunction. Leptin and adiponectin (APN) are two adipokines that are known to be associated with the pathogenesis of hypertension. However, how the level of these hormones is elevated in response to mechanical stretch in endothelial cells is yet to be elucidated.AimIn the present study, we investigated the expression of leptin and adiponectin in endothelial cells exposed to mechanical stretch.MethodsImmortalized human umbilical vein endothelial cells (EA. hy926) were subjected to mechanical stretch (15%, 60 cycle/min and 1Hz) using STREX cell stretching system (STREX Inc., California, USA) for 6, 16 and 24 h. Cultured cells not subjected to stretch (static condition) where used as controls. The mRNA expression of leptin and its receptor (OB‐Rb) as well as APN and adiponectin receptor 2 (APN‐R2) were assessed at different time points using real‐time PCR.ResultsMechanical stretch induced changes in cell morphology in which the cells were elongated and aligned perpendicular to the stretch axis. Stretching of endothelial cells significantly upregulated the expression of leptin after 16 h (0.9515 ± 0.4238‐fold, n=6, p&lt;0.05) and after 24 h (1.577 ± 0.4503‐fold, n=6, p&lt;0.05) of stretching but without affecting the expression of its receptor (OB‐Rb). The mRNA expression of APN also increased significantly in response to 6 h stretching (0.5457 ± 0.1890‐fold, n=6, p&lt;0.05), 16 h stretching (0.9487 ± 0.4058‐fold, n=6, p&lt;0.05) and 24 h stretching (2.664 ± 0.3447, n=6, p&lt;0.0001) compared to unstretched cells, however no change in the expression of APN‐R2 was observed.ConclusionOur findings suggesting that the exposure of endothelial cells to mechanical stretch can result in changes in the expression of adipokines, leptin and adiponectin, will result in better understanding of how vascular biology is affected by mechanical forces and how these molecules can modulate endothelial function in cardiovascular diseases.

ICA69 aggravates ferroptosis causing septic cardiac dysfunction via STING trafficking

Previous studies have demonstrated that cardiomyocyte apoptosis, ferroptosis, and inflammation participate in the progress of sepsis-induced cardiomyopathy (SIC). Although Islet cell autoantigen 69 (ICA69) is an imperative molecule that could regulate inflammation and immune response in numerous illnesses, its function in cardiovascular disease, particularly in SIC, is still elusive. We confirmed that LPS significantly enhanced the expression of ICA69 in wild-type (WT) mice, macrophages, and cardiomyocytes. The knockout of ICA69 in lipopolysaccharide(LPS)-induced mice markedly elevated survival ratio and heart function, while inhibiting cardiac muscle and serum inflammatory cytokines, reactive oxygen (ROS), and ferroptosis biomarkers. Mechanistically, increased expression of ICA69 triggered the production of STING, which further resulted in the production of intracellular lipid peroxidation, eventually triggering ferroptosis and heart injury. Intriguingly, ICA69 deficiency only reversed the ferroptotic marker levels, such as prostaglandin endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), 4-hydroxynonenal (4HNE), glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), iron and lipid ROS, but had no effects on the xCT-dependent manner. Additionally, greater ICA69 level was identified in septic patients peripheralblood mononuclear cells (PBMCs) than in normal control groups. Generally, we unveil that ICA69 deficiency can relieve inflammation and ferroptosis in LPS-induced murine hearts and macrophages, making targeting ICA69 in heart a potentially promising treatment method for SIC.

MiR-223-3p inhibits the progression of atherosclerosis via down-regulating the activation of MEK1/ERK1/2 in macrophages.

Background: microRNAs (miRNAs) have drawn more attention to the progression of atherosclerosis (AS), due to their noticeable inflammation function in cardiovascular disease. Macrophages play a crucial role in disrupting atherosclerotic plaque, thereby we explored the involvement of miR-223-3p in the inflammatory response in macrophages.Methods: RT-qPCR was used to analyze the miR-223-3p levels in carotid arteries and serum of AS patients. ROC curve was used to assess the diagnostic value of miR-223-3p. Movat staining was applied to evaluate the morphological differences. FISH was used to identify the expression of miR-223-3p in macrophages of atherosclerotic lesions. Bioinformatic analysis was performed. Double-immunofluorescence and western blot were performed to assess the inflammatory cytokine secretion and p-ERK1/2. C16-PAF was injected into the culture medium of the miR-223-3p mimic/NC-transfected macrophages with ox-LDL.Results: MiR-223-3p was up-regulated in AS patients and was associated with a higher overall survival rate. MiR-223-3p was co-localized with CD68+ macrophages in vulnerable atherosclerotic lesions. MiR-223-3p mimics decreased atherosclerotic lesions, macrophages numbers whereas increased SMCs numbers in the lesions. The TNF-a immune-positive areas were reduced by miR-223-3p mimics. MAP2K1 was negatively associated with miR-223-3p. MiR-223-3p mimics reduced the inflammation and the MEK1/ERK1/2 signaling pathway in vivo and in vitro. C16-PAF reversed the effects of miR-223-3p mimics on inflammation and ERK1/2 signaling pathway.Conclusions: MiR-223-3p negatively regulates inflammatory responses by the MEK1/ERK1/2 signaling pathway. Our study provides new insight into how miR-223-3p protects against atherosclerosis, representing a broader therapeutic prospect for treating atherosclerosis by miR-223-3p.

The Effect of Orlistat on Sterol Metabolism in Obese Patients.

BackgroundOrlistat, a reversible inhibitor of pancreatic and gastric lipase, is known to have anti-obesity and antioxidant properties. Cholesterol intermediates and metabolites have diverse and important functions in cardiovascular disease. Therefore, we aimed to evaluate the effect of orlistat on sterol metabolism in overweight and obese adults after weight loss during the intervention or weight loss at 12 weeks.MethodsA total of 51 (27 in the control group and 24 in the experimental group), patients with a BMI of 27 or greater were randomly assigned in a 1:1 ratio to receive either orlistat (120 mg) three times a day plus phentermine hydrochloride (37.5 mg) once daily or a placebo three times a day plus phentermine hydrochloride (37.5 mg) once daily. The primary study outcome was sterol metabolism.ResultsThe experimental group exhibited significantly decreased metabolic signatures of serum sterols, free cholesterol, sitosterol, 7α-hydroxycholesterol (7α-OHC), and 7β-OHC at 12 weeks. The experimental group also exhibited significantly decreased metabolic ratios of sitosterol and 7α-OHC to cholesterol at 12 weeks. Regarding changes in sterol signatures from baseline to 6-month follow-up, free cholesterol, plant sterols, and cholesterol precursors tended to decrease with weight loss during the intervention and increase again as the weight was regained in both groups.ConclusionOrlistat treatment improves oxysterol metabolism in overweight and obese adults. Our findings support that orlistat plays a crucial role in the process of endothelial dysfunction and atherosclerosis via oxysterol modulation.