Inflammatory Heart Research Articles

Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity

BackgroundDilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy.MethodsWe evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfβ/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment.ResultsCardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation.ConclusionsIn vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.Graphical

Excretory/secretory products from Trichinella spiralis adult worms ameliorate myocardial infarction by inducing M2 macrophage polarization in a mouse model

BackgroundIschemia-induced inflammatory response is the main pathological mechanism of myocardial infarction (MI)-caused heart tissue injury. It has been known that helminths and worm-derived proteins are capable of modulating host immune response to suppress excessive inflammation as a survival strategy. Excretory/secretory products from Trichinella spiralis adult worms (Ts-AES) have been shown to ameliorate inflammation-related diseases. In this study, Ts-AES were used to treat mice with MI to determine its therapeutic effect on reducing MI-induced heart inflammation and the immunological mechanism involved in the treatment.MethodsThe MI model was established by the ligation of the left anterior descending coronary artery, followed by the treatment of Ts-AES by intraperitoneal injection. The therapeutic effect of Ts-AES on MI was evaluated by measuring the heart/body weight ratio, cardiac systolic and diastolic functions, histopathological change in affected heart tissue and observing the 28-day survival rate. The effect of Ts-AES on mouse macrophage polarization was determined by stimulating mouse bone marrow macrophages in vitro with Ts-AES, and the macrophage phenotype was determined by flow cytometry. The protective effect of Ts-AES-regulated macrophage polarization on hypoxic cardiomyocytes was determined by in vitro co-culturing Ts-AES-induced mouse bone marrow macrophages with hypoxic cardiomyocytes and cardiomyocyte apoptosis determined by flow cytometry.ResultsWe observed that treatment with Ts-AES significantly improved cardiac function and ventricular remodeling, reduced pathological damage and mortality in mice with MI, associated with decreased pro-inflammatory cytokine levels, increased regulatory cytokine expression and promoted macrophage polarization from M1 to M2 type in MI mice. Ts-AES-induced M2 macrophage polarization also reduced apoptosis of hypoxic cardiomyocytes in vitro.ConclusionsOur results demonstrate that Ts-AES ameliorates MI in mice by promoting the polarization of macrophages toward the M2 type. Ts-AES is a potential pharmaceutical agent for the treatment of MI and other inflammation-related diseases.Graphical

Significance of catestatin in the pathogenesis of heart failure with preserved ejection fraction in patients with non-obstructive coronary artery disease

Aim. In patients with non-obstructive coronary artery disease (CAD), to evaluate the pathophysiological significance and diagnostic effectiveness of catestatin in detecting heart failure with preserved ejection fraction (HFpEF), as well as to assess the relationship of the levels of this biomarker with heart rate variability (HRV) parameters and the severity of diastolic dysfunction.Material and methods. The study included 83 patients (44 men, mean age, 62,0 [57,0; 68,5] years) with non-obstructive CAD and preserved left ventricular (LV) ejection fraction of 63 [60; 64]%). Echocardiography was performed according to a standard protocol. HRV was assessed using 24-hour electrocardiographic monitoring. Serum biomarker levels were determined using enzyme-linked immunosorbent assay.Results. Patients were divided into groups depending on HFpEF presence: group 1 (n=63) included patients with newly diagnosed HFpEF, and group 2 included patients without heart failure (n=20). Serum catestatin concentrations were 43,1% lower (p<0,001) in patients with HFpEF than in patients without it. Catestatin had a negative correlation with levels of N-terminal pro-brain natriuretic peptide and C-reactive protein. Moreover, serum catestatin values were inversely correlated with LV remodeling parameters, whereas no relationship was found with HRV values. According to ROC analysis, catestatin £132,83 μg/ml (AUC=0,884; p<0,001) were defined as threshold values associated with HFpEF.Conclusion. Decreased serum catestatin concentrations were associated with HFpEF and overexpression of heart failure and inflammation biomarkers. Moreover, serum catestatin values had a negative relationship with LV remodeling parameters, while no relationship was found with HRV values.

Black Goji Berry (Lycium ruthenicum Murray): A Review of Its Pharmacological Activity.

Lycium ruthenicum Murray (LRM; commonly known as black goji berry or black wolfberry), a plant in the Solanaceae family, grows in the deserts of China's Qinghai-Tibet plateau. LRM is widely consumed in traditional Chinese medicine, and its fruits are frequently used as herbal remedies to treat heart disease, fatigue, inflammation, and other conditions. Many studies have reported that LRM is rich in functional phytochemicals, such as anthocyanins and polysaccharides, and has various pharmacological actions. This article reviews research on the biological and pharmacological effects of the constituents of LRM fruits. LRM has various pharmacological properties, such as antioxidant, anti-inflammatory, anti-radiation, immune-enhancing, anti-tumor, and protective effects. LRM has much promise as a dietary supplement for preventing many types of chronic metabolic disease.

Myocardial edema, inflammation, and injury in human heart donated after circulatory death are sensitive to warm ischemia and subsequent cold storage

BackgroundSingle-dose del Nido solution was recently used in human donation after circulatory death (DCD) heart procurement. We compared the effect of del Nido cardioplegia on myocardial edema, inflammatory response, and injury in human DCD hearts and human donation after brain death (DBD) hearts with different warm ischemic times (WIT) and subsequent cold saline storage times (CST). MethodsA total of 24 human hearts, including 6 in the DBD group and 18 in the DCD group—were procured for the research study. The DCD group was divided into 3 subgroups based on WIT: 20, 40, and ≥60 minutes. All hearts received 1 L of del Nido cardioplegia before being placed in cold saline for 6 hours. Left ventricular biopsies were performed at 0, 2, 4, and 6 hours. Temporal changes in myocardial edema, inflammatory cytokines (TNF-α, IL-6, and IL-1β), and histopathology injury scores were compared between the DBD and DCD groups. ResultsDCD hearts showed more profound changes in myocardial edema, inflammation, and injury than DBD hearts at baseline and subsequent CST. The DCD heart with WIT of 20 and 40 minutes with CST of 4 and 2 hours, respectively, appeared to have limited myocardial edema, inflammation, and injury. DCD hearts with WIT ≥60 minutes showed severe myocardial edema, inflammation, and injury at baseline and subsequent CST. ConclusionsSingle-dose cold del Nido cardioplegia and subsequent cold normal saline storage can preserve both DCD and DBD hearts. DCD hearts have been shown to be able to tolerate a WIT of 20 minutes and subsequent CST of 4 hours without experiencing significant myocardial edema, inflammation, and injury.

Targeting of cold-inducible RNA-binding protein alleviates sepsis via alleviating inflammation, apoptosis and oxidative stress in heart.

A systemic inflammatory response is observed in patients undergoing shock and sepsis. This study aimed to explore the effects of cold-inducible RNA-binding protein (CIRP) on sepsis-associated cardiac dysfunction and the underlying mechanism. In vivo and in vitro lipopolysaccharide (LPS)-induced sepsis models were established in mice and neonatal rat cardiomyocytes (NRCMs), respectively. CRIP expressions were increased in the mouse heart and NRCMs treated with LPS. CIRP knockdown alleviated LPS-induced decreases of left ventricular ejection fraction and fractional shortening. CIRP downregulation attenuated the increases of inflammatory factors in the LPS-induced septic mouse heart, and NRCMs. The enhanced oxidative stress in the LPS-induced septic mouse heart and NRCMs was suppressed after CIRP knockdown. By contrast, CIRP overexpression yielded the opposite results. Our current study indicates that the knockdown of CIRP protects against sepsis-induced cardiac dysfunction through alleviating inflammation, apoptosis and oxidative stress of cardiomyocytes.

Sigma-1 receptor knockout disturbs gut microbiota, remodels serum metabolome, and exacerbates isoprenaline-induced heart failure.

Heart failure (HF) is usually the end stage of the continuum of various cardiovascular diseases. However, the mechanism underlying the progression and development of HF remains poorly understood. The sigma-1 receptor (Sigmar1) is a non-opioid transmembrane receptor implicated in many diseases, including HF. However, the role of Sigmar1 in HF has not been fully elucidated. In this study, we used isoproterenol (ISO) to induce HF in wild-type (WT) and Sigmar1 knockout (Sigmar1-/-) mice. Multi-omic analysis, including microbiomics, metabolomics and transcriptomics, was employed to comprehensively evaluate the role of Sigmar1 in HF. Compared with the WT-ISO group, Sigmar1-/- aggravated ISO-induced HF, including left ventricular systolic dysfunction and ventricular remodeling. Moreover, Sigmar1-/- exacerbated ISO-induced gut microbiota dysbiosis, which was demonstrated by the lower abundance of probiotics g_Akkermansia and g_norank_f_Muribaculaceae, and higher abundance of pathogenic g_norank_f_Oscillospiraceae and Allobaculum. Furthermore, differential metabolites among WT-Control, WT-ISO and Sigmar-/--ISO groups were mainly enriched in bile secretion, tryptophan metabolism and phenylalanine metabolism, which presented a close association with microbial dysbiosis. Corresponding with the exacerbation of the microbiome, the inflammation-related NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway were activated in the heart tissues. Taken together, this study provides evidence that a Sigmar1 knockout disturbs the gut microbiota and remodels the serum metabolome, which may exacerbate HF by stimulating heart inflammation.

Influence of fish on biochemical markers: A comparative study among male subjects of fish eaters and vegetarians

Introduction and Aim: Cardiovascular diseases (CVD) are the major causes of morbidity and mortality in India. Intake of a high or moderate amount of fish has shown a decreased risk of CVD. This is due to the presence of long-chain n-3 polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oils. According to past studies, regularly consuming these fatty acids lowers the risk of heart failure, myocardial infarction, endothelial dysfunction, inflammation, arrhythmias, and sudden death. The beneficial effects of a fish-rich diet appear to conflict with PUFA's susceptibility to oxidation. As a result, the study aimed to compare the lipid profile, cardiac markers, and lipid peroxidation status in male adults who consume moderate amounts of fish regularly. Materials and Methods: Total cholesterol (T.C.), HDL-cholesterol (HDL-C), triglycerides (T.G.), high sensitive C-reactive protein (hs-CRP), Lipoprotein (a) [Lp(a)], Malondialdehyde (MDA) and antioxidant activity (AOA) were measured in healthy male individual of 85 fish eaters and 77 vegetarians in the age group of 25-40 years. The atherogenic indices TC/ HDL-C, LDL-C/HDL-C, a Student's 't' test, and non-HDL-C/ HDL-C were determined. The two groups' parameters were compared using the Student's t-test. Results: In Fish eating male subjects, the lipid profile and cardiac markers were decreased except for HDL-C (which was increased). Fish eaters exhibited significant decreases in atherogenic indices, and significant variation was not observed in the oxidant status of the study groups (p>0.05). Conclusion: According to the present study's findings, regular intake of moderate amounts of fish is linked to a decrease in lipid profiles and cardiac markers without affecting the individual's oxidation status.

Abstract P2192: Growth Hormone-releasing Hormone Receptor Antagonist Attenuates Cardiopulmonary Injury Induced By A Bsl2 Rvsv-sars-cov-2-s Virus Mimic Of Sars-cov-2 Infectivity

Background: COVID-19 causes severe pulmonary injury that can lead to acute respiratory distress syndrome. Growth hormone-releasing hormone receptor (GHRH-R) and its splice variant are expressed in murine and human lung and heart. GHRH-R antagonist, MIA-602, has been shown to modulate cellular immune responses to bleomycin lung injury and decrease inflammation in models of sarcoid granuloma. Using the BSL2-friendly rVSV-SARS-CoV-2-S of K18 hACE2tg mice to mimic native SARS-CoV-2 infection, we tested our hypothesis that MIA-602 attenuates cardiopulmonary injury in this COVID-19 model. Methods: Male and female K18 hACE2tg mice were inoculated with SARS-CoV-2 Washington (WA-1) native strain, recombinant VSV-SARS-CoV-2-Spike virus (rVSV-SARS-CoV-2-S), or PBS and lung viral load, weight loss and histopathology compared between groups (N=5-8). K18 h ACE2 tg mice infected with rVSV-SARS-CoV-2-S were subject to daily subcutaneous injections of 10 μg MIA-602 or vehicle starting at 24h post-infection. Pulmonary function was measured via whole-body plethysmography on day 0, day 3, and day 5 (n=7). Five days after viral infection mice were sacrificed; and blood and tissues collected for histopathological analyses, H&E staining and ICAM-1 immunohistochemistry. T-test or One-way ANOVA-test was used for statistical analysis. Results: Native SARS-CoV-2 and rVSV-SARS-CoV-2-S presented with similar patterns of weight loss, infectivity (~60%) and histopathologic changes. Daily treatment with MIA-602 ameliorated weight loss, reduced lung perivascular inflammation and pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued respiratory rate, increased expiratory parameters (Te, PEF, EEP) and mitigated dysregulated measures of airway obstruction (Penh and Rpef) compared to vehicle. Conclusions: rVSV-SARS-CoV-2-S is an accurate and safe alternative to native SARS-CoV-2 for preclinical studies. Daily treatment with the synthetic peptide GHRH-R antagonist MIA-602 attenuates pulmonary dysfunction and heart inflammation in this new preclinical mouse model of COVID-19 pneumonia. We hypothesize that the molecular mechanism involves anti-inflammatory actions of MIA-602.

Abstract P3096: Nitric Oxide Supplementation During Cardiac Arrest Induces Inflammation And Apoptosis In Rat Hearts

Background: Neuroprotection during cardiac and aortic arch surgeries has been a topic of extensive concern. Several protocols were developed in the trial to achieve the best neurological outcome; amongst them is nitric oxide (NO) supplementation through extracorporeal membrane oxygenation (ECMO). While NO was shown to influence the neurological outcome when supplemented during cardiac surgeries, a little is known about the cardiac effects. The current study addresses the molecular effects associated with NO supplementation on the myocardium. Methods: Male Sprague Dawley rats (n=20, 450-550gm) were anesthetized and cooled with cardiopulmonary bypass (CPB) to a core temperature of 19±1 o C and maintained in hypothermic cardiac arrest for 30 minutes. Then, rats were rewarmed to a target temperature of 35 o C for 60 min using CPB without (control group, CPB), or with NO 20 ppm supplementation (experimental group). By the end of experiment, hearts were harvested and analyzed. Results: RNA sequencing analysis showed NO supplementation results in the differential expression of more the genes related to lipid metabolism, oxidative phosphorylation, inflammatory signaling, proteasome formation, autophagy, calcium handling, smooth muscle relaxation, and apoptotic response compared to the control group. RT-PCR confirmed the RNA sequencing analysis. The experimental group showed a six-fold increase in inflammatory markers IL-1 and NF-κβ. The control group showed increased expression of α1 and β1 adrenergic receptors, NO treatment has led to normalization of expression and a three-fold increase in β2 receptors expression compared to shams. NO supplementation induced apoptosis in the myocardium, as indicated by a 50% increase in TUNEL-positive nuclei compared to the control group. Conclusions: NO supplementation during cardiac arrest boosts the inflammatory response in the myocardium and is associated with increased apoptosis.

Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection

SARS‐CoV‐2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti‐viral drugs and monoclonal antibodies reduce early COVID‐19 severity, but treatments for late‐stage immuno‐thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus‐derived Serp‐1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic, and complement proteases as a self‐defense strategy to combat clearance. Serp‐1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp‐1 as a therapy for immuno‐coagulopathic complications during ARDS. Treatment with PEGSerp‐1 in two mouse‐adapted SARS‐CoV‐2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp‐1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase‐type plasminogen activator receptor (uPAR), thrombotic proteases, and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp‐1 is a highly effective immune‐modulator with therapeutic potential for severe viral ARDS, immuno‐coagulopathic responses, and Long COVID.

β-elemene alleviates hyperglycemia-induced cardiac inflammation and remodeling by inhibiting the JAK/STAT3-NF-κB pathway

BackgroundHyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. β-elemene (Ele) is a natural compound extracted from Curcuma Rhizoma and has anti-tumor effects. It also has therapeutic effects in some inflammatory diseases. However, the therapeutic effect of Ele on diabetic cardiomyopathy is not clear. The purpose of this study was to evaluate the effect of Ele on hyperglycemia-caused cardiac remodeling and heart failure. MethodsC57BL/6 mice were intraperitoneally injected with streptozotocin to induce DCM, and Ele was administered intragastric after 8 weeks to investigate the effect of Ele. RNA sequencing of cardiac tissue was performed to investigate the mechanism. ResultsEle markedly inhibited cardiac inflammation, fibrosis and hypertrophy in diabetic mice, as well as in high glucose-induced cardiomyocytes. RNA sequencing showed that cardioprotective effect of Ele involved the JAK/STAT3-NF-κB signaling pathway. Ele alleviated heart and cardiomyocyte inflammation in mice by blocking diabetes-induced JAK2 and STAT3 phosphorylation and NF-κB activation. ConclusionsThe study found that Ele preserved the hearts of diabetic mice by inhibiting JAK/STAT3 and NF-κB mediated inflammatory responses, suggesting that Ele is an effective therapy for DCM.

Bile acid binds heart failure and inflammation.

Bile acid binds heart failure and inflammation.

Sex and age differences in AMPK phosphorylation, mitochondrial homeostasis, and inflammation in hearts from inflammatory cardiomyopathy patients.

Linked to exacerbated inflammation, myocarditis is a cardiovascular disease, which may lead to dilated cardiomyopathy. Although sex and age differences in the development of chronic myocarditis have been postulated, underlying cellular mechanisms remain poorly understood. In the current study, we aimed to investigate sex and age differences in mitochondrial homeostasis, inflammation, and cellular senescence. Cardiac tissue samples from younger and older patients with inflammatory dilated cardiomyopathy (DCMI) were used. The expression of Sirt1, phosphorylated AMPK, PGC-1α, Sirt3, acetylated SOD2, catalase, and several mitochondrial genes was analyzed to assess mitochondrial homeostasis. The expression of NF-κB, TLR4, and interleukins was used to examine the inflammatory state in the heart. Finally, several senescence markers and telomere length were investigated. Cardiac AMPK expression and phosphorylation were significantly elevated in male DCMI patients, whereas Sirt1 expression remained unchanged in all groups investigated. AMPK upregulation was accompanied by a preserved expression of all mitochondrial proteins/genes investigated in older male DCMI patients, whereas the expression of TOM40, TIM23, and the mitochondrial oxidative phosphorylation genes was significantly reduced in older female patients. Mitochondrial homeostasis in older male patients was further supported by the reduced acetylation of mitochondrial proteins as indicated by acetylated SOD2. The inflammatory markers NF-κB and TLR4 were downregulated in older male DCMI patients, whereas the expression of IL-18 was increased in older female patients. This was accompanied by progressed senescence in older DCMI hearts. In conclusion, older women experience more dramatic immunometabolic disorders on the cellular level than older men.

#5566 DIETARY MAGNESIUM SUPPLEMENTATION REDUCES RENAL AND CARDIAC FIBROSIS IN AN EXPERIMENTAL MODEL OF TYPE 4 CARDIORENAL SYNDROME

Abstract Background and Aims In chronic kidney disease (CKD) patients, high serum phosphate (HP) levels are associated with the development of a cardiorenal renal syndrome type 4 (CRS4). In this syndrome, the heart is damaged by oxidative stress, inflammation, and fibrosis in renal tissue. In this study we have evaluated if dietary Mg supplementation could reduce CRS4. Method The in vivo studies were performed in 5/6Nx rats fed a high (0.9%) phosphate diet with high or low dietary content of Mg to evaluate: 1) The effect of dietary Mg supplementation (0.3%) on oxidative stress, inflammation and fibrosis of kidney and heart. 2) The contribution of hypomagnesemia (using a low Mg diet (0,03%) to the progression of CRS4 in Nx rats and normal rats as controls. 3) Whether dietary Mg supplementation (8 weeks) reduces renal and cardiac fibrosis in Nx rats with established CRS4. In vitro, we evaluated the effects of Mg (Mg2Cl) on mesangial and tubular cells and also cardiomyocytes cells expose to TGF-β. Results Dietary Mg supplementation (0,3%) improved renal function, decreased oxidative stress, FGF23 levels, hypertension, renal and cardiac fibrosis and recovered renal expression of Klotho. A low Mg diet increased FGF23 and renal fibrosis but a subsequent switch to dietary Mg supplementation did not significantly improve CRS4 parameters although it reduced the values of blood pressure. In HK2 and rat mesangial cells treated with TGFβ (100 ng/ml), high Mg levels (1,4- and 2,8-times basal levels in the medium) reduced the amount of pro-fibrotic proteins such as α-smooth muscle actin, fibronectin, or renin, recovering Klotho expression and decreasing Smad3 phosphorylation. Conclusion Dietary Mg supplementation is a useful tool to improve renal function and prevent CRS4, by reduction the progression of renal and cardiac fibrosis.

Retraction: Inhibition of Bcl2L12 attenuates eosinophilia-related inflammation in heart.

[This retracts the article DOI: 10.3389/fimmu.2020.01955.].

Ginsenoside Rg5 alleviates Ang II–induced cardiac inflammation and remodeling by inhibiting the JNK/AP-1 pathway

Increased level of Angiotensin II (Ang II) contributes to hypertensive heart failure via -hemodynamic and non-hemodynamic actions. Ginsenoside Rg5 (Rg5) occurs naturally in ginseng, which has shown various benefits for cardiovascular diseases. This study evaluated Rg5′s effects on Ang II-caused cardiac remodeling and heart failure. C57BL/6 mice developed hypertensive cardiac failure after four weeks of Ang II infusion. The mice were administered Rg5 via oral gavage for the last two weeks to investigate the potential mechanism of Rg5. RNA sequencing of heart tissues was performed for mechanistic studies. It was discovered that Rg5 inhibited cardiac inflammation, myocardial fibrosis, and hypertrophy, and prevented cardiac malfunction in mice challenged with Ang II, without altering blood pressure. RNA sequencing showed that Rg5′s cardioprotective effect involves the JNK/AP-1 signaling pathway. Rg5 diminished inflammation in mice hearts and cultured cardiomyocytes by blocking Ang II-activated JNK/AP-1 pathway. In the absence of JNK or AP-1 in cardiomyocytes, the anti-inflammatory effects of Rg5 were nullified. The study found that Rg5 preserved the hearts of Ang II-induced mice by reducing JNK-mediated inflammatory responses, suggesting that Rg5 is an effective therapy for hypertensive heart failure.

Cardiopreventive effect of Klotho protein on oxidative stress, inflammation and apoptosis during cardiac ischemia/reperfusion injury

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre, Poland. Background The injury of the myocardium during ischemia/reperfusion (IRI) involves metabolic, morphological and contractile disorders [1]. Klotho is a membrane or soluble anti-aging protein. Recent studies have proven the correlation of Klotho deficiency and the occurrence and development of cardiovascular diseases [2]. Purpose This study aimed to evaluate the effect of Klotho protein supply on oxidative stress, inflammation and apoptosis in hearts subjected to IRI. Methods Isolated Wistar rat hearts perfused with the Langendorff method were subjected to ischemia, followed by reperfusion, in the presence or absence of Klotho protein. Hemodynamic parameters, and the levels of nitrate/nitrite (NOX)-, glutathione peroxidase (GPx), superoxide dismutase (SOD), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Κb), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), interleukin-6 (IL-6), matrix metalloproteinase 2 (MMP-2), cytochrome c (cyt c) and caspase-9 were evaluated. Results Infusion supply of Klotho during IRI resulted in a recovery of contractile function (p=0.031) and heart rate (p=0.02). Klotho protein contributed to increase in the production of GPx (p=0.045) and SOD (p=0.006). The levels of (NOX)- (p=0.022), NF-Κb (p=0.006), NFATc1 (p=0.027), IL-6 (p=0.002), MMP-2 (p=0.008), cyt c (p=0.0002) and caspase-9 (p=0.009) were decreased in the IRI+Klotho group, as compared to the IRI group. Conclusions Klotho protein preserved heart mechanical function, enhanced antioxidant capacity, and reduced inflammation and apoptosis in the injured heart. Thus, Klotho can be recognized as a novel cardiopreventive/cardioprotective agent in ischemic damage.

Chemical constituents, pharmacological effects, toxicology, processing and compatibility of Fuzi (lateral root of Aconitum carmichaelii Debx): A review.

The lateral root of Aconitum carmichaelii Debx is known as Fuzi in Chinese. It is traditionally valued and used for dispelling cold, relieving pain effects, restoring 'Yang,' and treating shock despite its high toxicity. This review aims to provide comprehensive information on the chemical composition, pharmacological research, preparation, and compatibility of Fuzi to help reduce its toxicity and increase its efficiency, based on the scientific literature. In addition, this review will establish a new foundation for further studies on Fuzi. A systematic review of the literature on Fuzi was performed using several resources, namely classic books on Chinese herbal medicine and various scientific databases, such as PubMed, the Web of Science, and the China Knowledge Resource Integrated databases. Fuzi extracts contain diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloids types, and have various pharmacological activities, such as strong heart effect, effect on blood vessels, and antidepressant, anti-diabetes, anti-inflammatory, pain-relieving, antitumor, immunomodulatory, and other therapeutic effects. However, these extracts can also lead to various toxicities such as cardiotoxicity, neurotoxicity, reproductive toxicity, hepatotoxicity, and embryonic toxicity. In vivo and in vitro experiments have demonstrated that different processing methods and suitable compatibility with other herbs can effectively reduce the toxicities and increase the efficiency of Fuzi. The therapeutic potential of Fuzi has been demonstrated in conditions, such as heart failure, various pains, inflammation, and tumors, which is attributed to the diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloid types. In contrast, they are also toxic components. Proper processing and suitable compatibility can effectively reduce toxicity and increase the efficiency of Fuzi. Thus more pharmacological and toxicological mechanisms on main active compounds are necessary to be explored.

Cardiac disturbances and changes in tissue cytokine levels in mice fed with a high-refined carbohydrate diet

AimsThe consumption of highly refined carbohydrates increases systemic inflammatory markers, but its potential to exert direct myocardial inflammation is uncertain. Herein, we addressed the impact of a high-refined carbohydrate (HC) diet on mice heart and local inflammation over time. Main methodsBALB/c mice were fed with a standard chow (control) or an isocaloric HC diet for 2, 4, or 8 weeks (HC groups), in which the morphometry of heart sections and contractile analyses by invasive catheterization and Langendorff-perfused hearts were assessed. Cytokines levels by ELISA, matrix metalloproteinase (MMP) activity by zymography, in situ reactive oxygen species (ROS) staining and lipid peroxidation-induced TBARS levels, were also determined. Key findingsHC diet fed mice displayed left ventricular hypertrophy and interstitial fibrosis in all times analyzed, which was confirmed by echocardiographic analyses of 8HC group. Impaired contractility indices of HC groups were observed by left ventricular catheterization, whereas ex vivo and in vitro indices of contraction under isoprenaline-stimulation were higher in HC-fed mice compared with controls. Peak levels of TNF-α, TGF-β, ROS, TBARS, and MMP-2 occur independently of HC diet time. However, a long-lasting local reduction of the anti-inflammatory cytokine IL-10 was found, which was linearly correlated to the decline of systolic function in vivo. SignificanceAltogether, the results indicate that short-term consumption of HC diet negatively impacts the balance of anti-inflammatory defenses and proinflammatory/profibrotic mediators in the heart, which can contribute to HC diet-induced morphofunctional cardiac alterations.