Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease

Mesenchymal stem cells (MSCs) are the member of multipotency stem cells, which possess the capacity for self-renewal and multi-directional differentiation, and have several characteristics, including multi-lineage differentiation potential and immune regulation, which make them a promising source for cell therapy in inflammation, immune diseases, and organ transplantation. In recent years, MSCs have been described as a novel therapeutic strategy for the treatment of cardiovascular diseases because they are potent modulators of immune system with the ability to modulating immune cell subsets, coordinating local and systemic innate and adaptive immune responses, thereby enabling the formation of a stable inflammatory microenvironment in damaged cardiac tissues. In this review, the immunoregulatory characteristics and potential mechanisms of MSCs are sorted out, the effect of these MSCs on immune cells is emphasized, and finally the application of this mechanism in the treatment of cardiovascular diseases is described to provide help for clinical application.

miR-190a-5p Partially Represses the Abnormal Electrical Activity of SCN3B in Cardiac Arrhythmias by Downregulation of IL-2

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by miR-190a-5p in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence in situ hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that miR-190a-5p to be downregulated. Luciferase reporter assay, quantitative real-time-PCR, and whole-cell patch-clamp experiments confirmed the downregulation of IL-2 by miR-190a-5p and influence of the latter on the sodium current of SCN3B. Overall, miR-190a-5p suppressed the increase in SCN3B sodium current caused by endogenous IL-2, whereas miR-190a-5p inhibitor significantly reversed this effect. IL-2 was demonstrated to be directly regulated by miR-190a-5p. We, therefore, concluded that the miR-190a-5p/IL-2/SCN3B pathway could be involved in the pathogenesis of CAs and miR-190a-5p might acts as a potential protective factor in pathogenesis of CAs.

Herbal Products for Management of COVID- 19

COVID-19 is a human-infectious virus. The respiratory system is the primary target of the coronavirus, but it can also harm cardiac tissues and gastrointestinal organs. Many frequent circumstances, such as the medication's or medicine's purpose, the dosage/potency of the drug, and the patient's condition, can place patients in grave danger. Several cures have been reported using a variety of therapy methods. Among the various treatments, natural and synthetic medicines are the most commonly documented. Some herbal medicines, such as Tribulusterrestris, Withaniasomnifera, Curcuma longa, Ocimum sanctum, and Phyllanthusemblica, have powerful antiviral (AntiCOV-19) properties against novel coronavirus, heralding the start of a new era in herbal therapy.

The Diagnostic and Prognostic Value of Plasma Galectin 3 in HFrEF Related to the Etiology of Heart Failure

Aim: The aim of present study is to evaluate the diagnostic and prognostic value of plasma galectin 3 (Gal-3) for HF originating from different causes.Methods: We investigated the plasma levels and expression of Gal-3 in cardiac tissues in two transgenic (TG) strains of mice with cardiomyocyte-restricted overexpression of either β2- adrenergic receptor (β2- AR TG) or Mammalian sterile 20-like kinase 1 (Mst1-TG) in the present study. Additionally, 166 patients suffering from heart failure with reduced ejection fraction (HFrEF) in two hospitals within the Shaanxi province were examined in this study. All these patients were treated according to the Chinese HF guidelines of 2014; subsequently, they were followed up for 50 months, and we analyzed the prediction value of baseline Gal-3 to endpoints in these patients.Results: Gal-3 was localized in the cytoplasm and nucleus of cardiomyocytes, often formed aggregates in Mst1-TG mice. Extracellular Gal-3 staining was uncommon in Mst1-TG hearts. However, in β2-AR TG mice, although Gal-3 was also expressed in myocardial cells, it was more highly expressed in interstitial cells (e.g., fibroblasts and macrophages). Plasma Gal-3 was comparable between nTG and Mst1-TG mice. However, plasma Gal-3 was higher in β2-AR TG mice than in nTG mice. In the cohort of HFrEF patients, the median plasma Gal-3 concentration was 158.42 pg/mL. All participants were divided into two groups according to Gal-3 levels. Patients with Gal-3 concentrations above the median were older, and had lower plasma hemoglobin, but higher plasma creatinine, tissue inhibitor of metalloproteinases 1 (TIMP-1), left ventricular end systolic diameter (LVESD), left ventricular end-systolic volumes (LVESV) and end-diastolic, as well as left ventricular end-diastolic volumes (LVEDV). Spearman correlation analysis revealed that Gal-3 was positively correlated with TIMP-1 (r = 0.396, P < 0.001), LVESV (r = 0.181, P = 0.020) and LVEDV (r = 0.190, P = 0.015). The 50-month clinical follow-up revealed 43 deaths, 97 unplanned re-hospitalizations, and 111 composite endpoint events. Cox analysis demonstrated that although Gal-3 did not provide any prognostic value in either total-HF subjects or coronary-heart-disease (CHD) patients, it did provide prognostic value in non-CHD patients.Conclusion: Although plasma Gal-3 is associated with TIMP-1 and echocardiographic parameters, the diagnostic and prognostic value of Gal-3 in HFrEF is determined by the etiology of HF.

Buccal Mucosa Cells as a Potential Diagnostic Tool to Study Onset and Progression of Arrhythmogenic Cardiomyopathy

In arrhythmogenic cardiomyopathy (ACM) pathogenic variants are found in genes encoding desmosomal proteins and in non-desmosomal genes, such as phospholamban (PLN, p.Arg14del variant). Previous research showed that plakoglobin protein levels and localization in the cardiac tissue of ACM patients, and PLN p.Arg14del patients diagnosed with an ACM phenotype, are disturbed. Moreover, the effects of pathogenic variants in desmosomal genes are reflected in non-cardiac tissues like buccal mucosa cells (BMC) which could serve as a promising new and non-invasive tool to support diagnosis. We collected the BMC of 33 ACM patients, 17 PLN p.Arg14del patients and 34 controls, labelled the BMC with anti-plakoglobin antibodies at different concentrations, and scored their membrane labelling. We found that plakoglobin protein levels were significantly reduced in BMC obtained from diagnosed ACM patients and preclinical variant carriers when compared to controls. This effect was independent from age and sex. Moderate to strong correlations were found with the revised 2010 Task Force Criteria score which is commonly used for ACM diagnosis (rs = −0.67, n = 64, p < 0.0001 and rs = −0.71, n = 64, p < 0.0001). In contrast, plakoglobin scores in PLN p.Arg14del patients were comparable to controls (p > 0.209), which suggests differences in underlying etiology. However, for the individual diagnosis of the ‘classical’ ACM patient, this method might not be discriminative enough to distinguish true patients from variant carriers and controls, because of the high interindividual variability.

A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection

Early-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection. At five weeks post HIV infection, Hu-mice developed grade III-IV diastolic dysfunction (DD) with an associated two-fold increase in plasma MG. At sixteen-seventeen weeks post infection, cardiac ejection fraction and fractional shortening also declined by 26 and 35%, and plasma MG increased to four-fold higher than uninfected controls. Histopathological and biochemical analyses of cardiac tissues from Hu-mice 17 weeks post-infection affirmed MG increase with a concomitant decrease in expression of the MG-degrading enzyme glyoxalase-1 (Glo1). The endothelial cell marker CD31 was found to be lower, and coronary microvascular leakage and myocardial fibrosis were prominent. Increasing expression of Glo1 in Hu-mice five weeks post-infection using a single dose of an engineered AAV2/9 (1.7 × 1012 virion particles/kg), attenuated the increases in plasma and cardiac MG levels. Increasing Glo1 also blunted microvascular leakage, fibrosis, and HF seen at sixteen weeks post-infection, without changes in plasma viral loads. In plasma from virally suppressed PLWH, MG was also 3.7-fold higher. In autopsied cardiac tissues from seropositive, HIV individuals with low viral log, MG was 4.2-fold higher and Glo1 was 50% lower compared to uninfected controls. These data show for the first time a causal link between accumulation of MG and HF in the setting of HIV infection.

CB2 receptor agonist and L- arginine combination attenuates diabetic cardiomyopathy in rats via NF-ĸβ inhibition

Beta-caryophyllene (BCP), a cannabinoid 2 receptor (CB2) agonist has recently been found to have cardioprotective activity as an anti-inflammatory and antioxidant molecule. L-arginine (LA), a nitric oxide (NO) donor is a potential regulator of cardiovascular function. Considering the role of CB2 receptor activation and NO regulation in cardiovascular diseases, the combination of BCP with LA may be a possible treatment of diabetic cardiomyopathy (DCM). Hence, we investigated the efficacy of the novel combination of BCP with LA on cardiovascular inflammation and oxidative stress in diabetic rats. DCM was induced by Streptozotocin (55 mg/kg) in SD rats intraperitoneally. BCP, LA and BCP with LA were administered to diabetic rats for 4 weeks. After completion of the study, hemodynamic parameters, biochemical parameters, and inflammatory cytokine levels were analyzed. Also, oxidative stress parameters, NF-ĸβ expression and histopathology in cardiac tissues were estimated. The combination of BCP (200 mg/kg) with LA (200 mg/kg) significantly normalized the hemodynamic parameters and decreased the glucose, cardiac markers, IL-6 and TNF-α levels. Treatment of BCP and LA showed a significant decrease in oxidative stress and down-regulated the cardiac expression of NF-ĸβ. Thus, the combination of BCP with LA improves cardiac functions by attenuating inflammation through NF-ĸβ inhibition in DCM.

Dynamics of spiral waves and bubble formation in a closed chemical system of thin photosensitive excitable media

Spiral waves have been observed in a thin layer of excitable media. Especially, electrical spiral waves in cardiac tissues connect to cardiac tachycardia and life-threatening fibrillations. The Belousov-Zhabotinsky (BZ) reaction is the most widely used system to study the dynamics of spiral waves in experiments. When the light sensitive Ru(bpy)3 2+ is used as the catalyst, the BZ reaction becomes photosensitive and the excitability of the reaction can be controlled by varying the illumination intensity. However, the typical photosensitive BZ reaction produces many CO2 bubbles so the spiral waves are always studied in thin layer media with opened top surfaces to release the bubbles. In this work, we develop new chemical recipes of the photosensitive BZ reaction which produces less bubbles. To observe the production of bubbles, we investigate the dynamics of spiral waves in a closed thin layer system. The results show that both the speed of spiral waves and the number of bubbles increase with the concentration of sulfuric acid (H2SO4) and sodium bromate (NaBrO3). For high initial concentrations of both reactants, the size of bubbles increases with time until the wave structures are destroyed. We expect that the chemical recipes reported here can be used to study complicated dynamics of three-dimensional spiral waves in thick BZ media where the bubbles cannot escape.

88 Differential cardiotoxicity of immune checkpoint inhibitors involves damps fibronectin-EDA, calgranulin, galectine-3, and associated nlrp3 inflammasome-interleukins pathway in preclinical models

Aims Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy, opening to advantages in cancer outcomes. However, several ICIs-induced side effects emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We analysed the differential vasculo and cardiotoxicity of Pembrolizumab, Nivolumab and Ipilimumab in preclinical models highlighting on the molecular pathways involved. Methods C57 female mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injection for 10 days. Before and after treatments, analysis of fractional shortening, ejection fraction, radial and longitudinal strain was performed through 2D-echocardiography (Vevo 2100, Visual Sonics Fujfilm). Fibrosis, necrosis, hypertrophy and vascular/myocardial NF-kB expression were analysed through Immunohistochemistry (IHC). DAMPs, NLRP3, MyD88, p65/NF-kB and 12 cytokines have been analysed in murine myocardium and in cardiomyocytes co-incubated with hPBMC. Results In preclinical models, treatment with Nivolumab leads to increased vascular and myocardial NF-kB expression without affecting fibrosis unlike Ipilimumab which also increases cardiac collagen production. Pembrolizumab increased myocardial hypertrophy and fibrosis in cardiac tissues with a strong vascular NF-kB expression. All tested ICIs increased DAMPs, NLRP3 inflammasome-IL1β-IL18 axis and only Pembrolizumab increased significantly the MyD88 expression vs. untreated mice. Conclusions In preclinical models, Pembrolizumab exerts the most relevant cardiotoxicity compared to Nivolumab and Ipilimumab, increasing immune infiltration in the myocardium and vascular inflammation. All tested ICIs increased DAMPs, NLRP3/IL-1β and MyD88 expression, leading to pro-inflammatory cytokine storm in heart tissues.

Induction of Caveolin-3/RyR2 By Liraglutide Ameliorates Diabetic Cardiomyopathy

Background Liraglutide (LIRA), a Glucagon-like peptide-1 receptor agonist (GLP-1RA), showed potent cardioprotective effects with the mechanism remained incompletely understood. Caveolin-3 (Cav3) is the cardiomyocytes specific caveolae structural protein, decreased in the diabetic heart. Therefore, this study aimed to investigate whether LIRA exerts its effect on cardiac function in rats with type 2 diabetes mellitus (T2DM) via enhance Cav3 expression. Methods T2DM rats were used as study subjects and randomly divided into four groups: 1) CON group, 2) CON+L group, 3) DM group and 4) DM+L group. All rats received either saline or LIRA 0.2 mg/kg (by i.p injection) per day for 4 weeks. After the model was successfully established, cardiac function was determined by invasive hemodynamic evaluation methods. Immunohistochemistry and western blot were performed to understand the molecular mechanism between cardiac function and LIRA. Results Based on our results, DM group displayed higher blood glucose than Con group (20.57±2.75 mol/L vs. 4.34±0.21 mol/L), while blood glucose level in DM+L group was lower than DM group after received LIRA (10.36±1.84 mol/L). LVSP (91.39±4.98 mmHg), LV +dp/dtmax (4040.74±197.72 mmHg/s) were significantly reduced in DM group, and diabetic rats also exhibited reduced -dp/dtmax (2926.5±142.3 mmHg/s) and elevated LVEDP (10.87±0.83 mmHg). LIRA treatment showed a trend to enhance LVSP (110.76±5.61 mmHg) and ± dp/dtmax (5860.41±200.32 mmHg and 3996.8±179.3 mmHg), decreased LVEDP (7.23±0.58 mmHg). The expression of Cav3, eNOS and RyR2 was significantly decreased in the myocardium in DM group, which increased in DM+L group after LIRA administrated. Hemodynamic data showed DM rats exhibited impairment of myocardial function, while LIRA improved cardiac systolic and diastolic function, attenuate diabetic cardiomyopathy injury by improving Cav3/eNOS/NO signaling, reducing ROS level in cardiac tissues, and increasing interaction of Cav3 and ryanodine receptor 2 (RyR2). Conclusions Liraglutide ameliorates cardiac dysfunction in rats with type 2 diabetes mellitus via reducing ROS level in cardiac tissues, improving Cav3/eNOS/NO signaling and increasing interaction of Cav3 and RyR2. Keywords Type-2 diabetes Mellitus, liraglutide, caveolin-3, ryanodine receptor2, myocardial dysfunction