Neocryptotanshinone ameliorates insufficient energy production in heart failure by targeting retinoid X receptor alpha.

Retinoid X receptor alpha (RXRα) is a nuclear transcription factor that extensively regulates energy metabolism in cardiovascular diseases. Identification of targeted RXRα drugs for heart failure (HF) therapy is urgently needed. Neocryptotanshinone (NCTS) is a component derived from Salvia miltiorrhiza Bunge, the effect and mechanism of which for treating HF have not been reported. The goal of this study was to explore the pharmacological effects of NCTS on energy metabolism to protect against HF post-acute myocardial infarction (AMI) via RXRα. We established a left anterior descending artery ligation-induced HF post-AMI model in mice and an oxygen-glucose deprivation-reperfusion-induced H9c2 cell model to investigate the cardioprotective effect of NCTS. Component-target binding techniques, surface plasmon resonance (SPR), microscale thermophoresis (MST) and small interfering RNA (siRNA) transfection were applied to explore the potential mechanism by which NCTS targets RXRα. The results showed that NCTS protects the heart against ischaemic damage, evidenced by improvement of cardiac dysfunction and attenuation of cellular hypoxic injury. Importantly, the SPR and MST results showed that NCTS has a high binding affinity for RXRα. Meanwhile, the critical downstream target genes of RXRα/PPARα, which are involved in fatty acid metabolism, including Cd36 and Cpt1a, were upregulated under NCTS treatment. Moreover, NCTS enhanced TFAM levels, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate levels by activating RXRα. In conclusion, we confirmed that NCTS improves myocardial energy metabolism, including fatty acid oxidation and mitochondrial biogenesis, by regulating the RXRα/PPARα pathway in mice with HF post-AMI.

A Pharmacological Review of Tanshinones, Naturally Occurring Monomers from Salvia miltiorrhiza for the Treatment of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are a set of heart and blood vessel disorders that include coronary heart disease (CHD), rheumatic heart disease, and other conditions. Traditional Chinese Medicine (TCM) has definite effects on CVDs due to its multitarget and multicomponent properties, which are gradually gaining national attention. Tanshinones, the major active chemical compounds extracted from Salvia miltiorrhiza, exhibit beneficial improvement on multiple diseases, especially CVDs. At the level of biological activities, they play significant roles, including anti-inflammation, anti-oxidation, anti-apoptosis and anti-necroptosis, anti-hypertrophy, vasodilation, angiogenesis, combat against proliferation and migration of smooth muscle cells (SMCs), as well as anti-myocardial fibrosis and ventricular remodeling, which are all effective strategies in preventing and treating CVDs. Additionally, at the cellular level, Tanshinones produce marked effects on cardiomyocytes, macrophages, endothelia, SMCs, and fibroblasts in myocardia. In this review, we have summarized a brief overview of the chemical structures and pharmacological effects of Tanshinones as a CVD treatment to expound on different pharmacological properties in various cell types in myocardia.

Neocryptotanshinone protects against myocardial ischemia-reperfusion injury by promoting autolysosome degradation of protein aggregates via the ERK1/2-Nrf2-LAMP2 pathway.

BACKGROUND: Aggrephagy is a critical compensatory mechanism for the elimination of misfolded proteins resulting from stress and depends on the autolysosome degradation of protein aggregates. However, there have been few mechanism research related to aggrephagy in myocardial ischemia/reperfusion (I/R) injury. Neocryptotanshinone (NCTS) is a fat-soluble active compound extracted from Salvia miltiorrhiza, and may be cardioprotective against I/R. However, the efficacy and specific mechanism of NCTS on I/R have not been studied. PURPOSE: The current study aimed to investigate the molecular mechanism of NCTS involved in the therapeutic effect on I/R, with a special emphasis on the up-regulation of the ERK1/2-Nrf2-LAMP2 pathway to increase autolysosomal degradation during aggrephagy. METHODS: A rat model of myocardial I/R injury was constructed by left anterior descending (LAD) ligation-reperfusion. To verify cardiac protection, autolysosome clearance of protein aggregates, and their intracellular biological mechanism, an oxygen-glucose deprivation/recovery (OGD/R)-induced H9c2 cardiomyocyte model was created. RESULTS: NCTS was found to have a significant cardioprotective effect in I/R rats as evidenced by remarkably improved pathological anatomy, decreased myocardial damage indicators, and substantially enhanced cardiac performance. Mechanistically, NCTS might boost the levels of LAMP2 mRNA and protein, total and Ser40 phosphorylated Nrf2, and Thr202/Tyr204p-ERK1/2 protein. Simultaneously, the cytoplasmic Nrf2 level was reduced after NCTS administration, which was contrary to the total Nrf2 content. However, these beneficial changes were reversed by the co-administration with ERK1/2 inhibitor, PD98059. NCTS therapy up-regulated Rab7 protein content, Cathepsin B activity, and lysosomal acidity, while down-regulating autophagosome numbers, Ubiquitin (Ub), and autophagosome marker protein accumulations through the above signaling pathway. This might indicate that NCTS enhanced lysosomal fusion and hydrolytic capacity. It was also found that NCTS intervention limited oxidative stress and cellular apoptosis both in vivo and in vitro. CONCLUSIONS: We reported for the first time that NCTS promoted the autolysosome removal of protein aggregation both in vivo and in vitro, to exert the therapeutic advantages of myocardial I/R injury. This was reliant on the up-regulation of the ERK1/2-Nrf2-LAMP2 signaling pathway.

Ginsenoside Rb3 upregulates sarcoplasmic reticulum Ca2+-ATPase expression and improves the contractility of cardiomyocytes by inhibiting the NF-κB pathway.

A causal relationship between ginsenoside Rb3 (G-Rb3) and improved inflammation and cardiac function has not been established. To determine which specific signaling pathways were involved in G-Rb3 improvement of inflammation and myocardial function. In vivo, we found that G-Rb3 decreased the levels of both nuclear factor κB (NF-κB p65) and CD45, an inflammatory marker. G-Rb3 also enhanced key proteins of the contraction unit (cardiac troponin protein I (cTnI) and α-actinin) to improve cardiac function. G-Rb3 inhibited NF-κB p65 nuclear translocation in vitro, as verified by western blot and IF. When NF-κB p65 was overexpressed, a decrease in cyclic nucleotide phosphodiesterase 3B (PDE3B) and SERCA2a expression, while no statistical significance was observed in the expressions of cAMP, PKA, and calcium/calmodulin-dependent protein kinase type II (CaMKⅡ) in each group. The NF-κB p65 plasmid blocked the SERCA2a promoter, as verified by the luciferase reporter system, and G-Rb3 truncated the NF-κB p65 block on the SERCA2a promoter. qPCR was also used to confirm that G-Rb3 increased the mRNA of SERCA2a. In conclusion, we confirmed that the mechanisms of G-Rb3 on ventricular systolic dysfunction causing inflammation are not via the cAMP/PKA pathway, but via suppressing the blockage of NF-κB p65 on the SERCA2a promoter and increasing the SERCA2a expression.

Exercise and Circulating Microparticles in Healthy Subjects.

This study aimed to explore the relationship between exercise and circulating microparticles (CMPs). PubMed, Web of Science, Embase, and the Cochrane Library databases were searched until August 13, 2020, using the terms "exercise" and "cell-derived microparticles." The Cochrane tool of risk of bias and the Methodological Index for Non-Randomized Studies were used to grade the studies. Twenty-six studies that met criteria were included in this review, including one before-after self-control study, 2 cohort studies, 4 randomized control trials, 5 case-control studies, and 14 descriptive studies. The studies were divided into a single bout and long-term exercise. The types of MPs contained endothelium-derived microparticles (EMPs), leukocyte-derived microparticles (LMPs), platelet-derived microparticles (PMPs), and erythrocyte-derived microparticles (ErMPs). This first systematic review found that the levels of CMPs continued to increase after a single bout of exercise in untrained subjects and were lower in trained subjects. PMPs expressed a transient increase after a single bout of exercise, and the proportion and duration of PMPs increment reduced in long-term exercise. Most studies showed a decline in LMPs in trained subjects after a single bout and long-term exercise, and variable changes were found in EMPs and ErMPs after exercise. A single bout of exercise drives the vessels exposed to high shear stress that promotes the formation of CMPs. However, the decline in CMPs in trained subjects may be attributed to the fact that they have a better ability to adapt to changes in hemodynamics and cellular function during exercise.

Qiliqiangxin Capsules Optimize Cardiac Metabolism Flexibility in Rats With Heart Failure After Myocardial Infarction.

Metabolic modulation is a promising therapy for ischemic heart disease and heart failure. This study aimed to clarify the regional modulatory effect of Qiliqiangxin capsules (QLQX), a traditional Chinese medicine, on cardiac metabolic phenotypes. Sprague-Dawley rats underwent left anterior descending coronary artery ligation and were treated with QLQX and enalapril. Striking global left ventricular dysfunction and left ventricular remodeling were significantly improved by QLQX. In addition to the posterior wall, QLQX also had a unique beneficial effect on the anterior wall subject to a severe oxygen deficit. Cardiac tissues in the border and remote areas were separated for detection. QLQX enhanced the cardiac 18F-fluorodeoxyglucose uptake and the levels and translocation of glucose transport 4 (GLUT4) in the border area. Meanwhile, it also suppressed glucose transport 1 (GLUT1) in both areas, indicating that QLQX encouraged border myocytes to use more glucose in a GLUT4-dependent manner. It was inferred that QLQX promoted a shift from glucose oxidation to anaerobic glycolysis in the border area by the augmentation of phosphorylated pyruvate dehydrogenase, pyruvate dehydrogenase kinases 4, and lactic dehydrogenase A. QLQX also upregulated the protein expression of fatty acid translocase and carnitine palmitoyl transferase-1 in the remote area to possibly normalize fatty acid (FA) uptake and oxidation similar to that in healthy hearts. QLQX protected global viable cardiomyocytes and promoted metabolic flexibility by modulating metabolic proteins regionally, indicating its potential for driving the border myocardium into an anaerobic glycolytic pathway against hypoxia injuries and urging the remote myocardium to oxidize FA to maximize energy production.

Comparison of different protocols of Morris water maze in cognitive impairment with heart failure.

AIM: This study aimed to find a more sensitive and systematic behavioral evaluation protocol to evaluate the cognitive impairment in rats with heart failure (HF). METHODS AND RESULTS: An HF rat model was built by ligating the left anterior descending coronary artery. The cardiac function and structure were detected using echocardiography. Myocardial histopathological changes were observed by nitro blue tetrazolium and hematoxylin-eosin staining. The cognitive functions were evaluated using the acquisition task, probe trial, reversal test, and matching-to-sample test of the Morris water maze. In the probe trial, the number of times the rats in the model group crossed the platform site significantly decreased compared with that in the sham group. In the reversal test, the average latency was significantly longer in the sham group compared with the model group in the first trial but was shorter in the second and third trials. In the matching-to-sample test, the average latency of Trial1 increased significantly in the model group compared with the sham group, while no obvious difference was observed in Trial2. Therefore, the difference in the average latency between Trial1 and Trial2 of the model group was significantly larger. CONCLUSIONS: The cognitive impairment in rats with HF mainly reflected in the long-term and working memory, spatial learning, and reversal learning ability. The probe trial and reversal test in the water maze may be more sensitive and preferred to evaluate cognitive function after HF. These findings would provide a brief evaluation protocol for further studies on the relationship between cognitive function and HF.

Dynamic Changes in Brain Glucose Metabolism and Neuronal Structure in Rats with Heart Failure.

Patients with heart failure (HF) are more susceptible to cognitive impairment, but the mechanism is still unclear. This study aimed to observe the dynamic changes in brain glucose metabolism and neuronal structure in different stages of HF. An HF rat model was established by ligating the anterior descending branch of the left coronary artery. To simulate acute heart failure (AHF) and chronic heart failure (CHF) in the clinic, relevant laboratory indexes were detected 10 and 60 days after ligation. The results showed that the model rats had systolic HF. Cognitive function was not obviously impaired in 10-day rats with HF, while the memory and learning functions were significantly impaired in 60-day rats with HF. The brain glucose metabolism in 10-day rats compensatorily increased in the prefrontal cortex (PFC), medial PFC (mPFC), cingulate gyrus, and basal ganglia (BG). In contrast, the metabolism of 60-day rats reduced in the PFC and BG. Meanwhile, the neuronal structure slightly changed in 10-day rats with HF, but neuronal karyopyknosis, reduced Nissl bodies, and swollen organelles were found in 60-day rats with HF. In conclusion, brain glucose metabolism and neuronal structure showed a dynamic evolution. Rats with AHF were in a compensatory state for increased glucose metabolism and slight neuronal damage. As a result, no significant cognitive impairment was observed. However, rats with CHF had significantly decreased cerebral glucose metabolism and neuronal degeneration, contributing to the cognitive function after HF.

The Level of Circulating Microparticles in Patients with Coronary Heart Disease: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: To assess the correlation between microparticles (MPs) and subgroups of coronary heart disease (CHD), including stable angina (SA), unstable angina (UA), and myocardial infarction (MI). METHODS: A literature search was carried out systematically to identify available case-control studies. The level of MPs was compared and MPs' merged standardized mean differences (SMDs) were pooled for the meta-analysis. RESULTS: Six studies met the inclusion criteria and were used for systematic review and meta-analysis. The level of MPs was higher in patients with CHD than that in the NS (normal subjects) group (SMD 2.28; 95% confidence interval (CI) 1.70-2.85; P = 0.000), and was also significantly different in subgroups of CHD (UA vs SA: SMD 2.35, 95% CI 1.56-3.14, P = 0.000; MI vs SA: SMD 3.08, 95% CI 2.07-4.09, P = 0.000; MI vs UA: SMD 0.83, 95% CI 0.41-1.26, P = 0.000). The similar results were also found in subgroups analyses of CD31+CD42- endothelium-derived microparticles (EMPs) and CD144+EMPs. CONCLUSION: The level of MPs, especially CD31+CD42-EMPs and CD144+EMPs, had an increasing trend with the degree of CHD: NS

Effects of febuxostat on atrial remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing.

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase (XO), may be used in the prevention and management of atrial fibrillation (AF). The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing (RAP) and the mechanisms by which it acts. METHODS: Twenty-four rabbits were randomly divided into four groups: sham-operated group (Group S), RAP group (Group P), RAP with 5 mg/kg per day febuxostat group (Group LFP), and RAP with 10 mg/kg per day febuxostat group (Group HFP). All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks. The effects of febuxostat on atrial electrical and structural remodeling, markers of inflammation and oxidative stress, and signaling pathways involved in the left atrium were examined. RESULTS: Shortened atrial effective refractory period (AERP), increased AF inducibility, decreased mRNA levels of Cav1.2 and Kv4.3, and left atrial enlargement and dysfunction were observed in Group P, and these changes were suppressed in the groups treated with febuxostat. Prominent atrial fibrosis was observed in Group P, as were increased levels of TGF-ß1, Collagen I, and α-SMA and decreased levels of Smad7 and eNOS. Treatment with febuxostat attenuated these differences. Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat. CONCLUSIONS: This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-ß1/Smad signaling pathway.

Diagnostic Performance of a Smart Device With Photoplethysmography Technology for Atrial Fibrillation Detection: Pilot Study (Pre-mAFA II Registry).

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The asymptomatic nature and paroxysmal frequency of AF lead to suboptimal early detection. A novel technology, photoplethysmography (PPG), has been developed for AF screening. However, there has been limited validation of mobile phone and smart band apps with PPG compared to 12-lead electrocardiograms (ECG). OBJECTIVE: We investigated the feasibility and accuracy of a mobile phone and smart band for AF detection using pulse data measured by PPG. METHODS: A total of 112 consecutive inpatients were recruited from the Chinese PLA General Hospital from March 15 to April 1, 2018. Participants were simultaneously tested with mobile phones (HUAWEI Mate 9, HUAWEI Honor 7X), smart bands (HUAWEI Band 2), and 12-lead ECG for 3 minutes. RESULTS: In all, 108 patients (56 with normal sinus rhythm, 52 with persistent AF) were enrolled in the final analysis after excluding four patients with unclear cardiac rhythms. The corresponding sensitivity and specificity of the smart band PPG were 95.36% (95% CI 92.00%-97.40%) and 99.70% (95% CI 98.08%-99.98%), respectively. The positive predictive value of the smart band PPG was 99.63% (95% CI 97.61%-99.98%), the negative predictive value was 96.24% (95% CI 93.50%-97.90%), and the accuracy was 97.72% (95% CI 96.11%-98.70%). Moreover, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of mobile phones with PPG for AF detection were over 94%. There was no significant difference after further statistical analysis of the results from the different smart devices compared with the gold-standard ECG (P>.99). CONCLUSIONS: The algorithm based on mobile phones and smart bands with PPG demonstrated good performance in detecting AF and may represent a convenient tool for AF detection in at-risk individuals, allowing widespread screening of AF in the population. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-OOC-17014138; http://www.chictr.org.cn/showproj.aspx?proj=24191 (Archived by WebCite at http://www.webcitation/76WXknvE6).

[Huotan Jiedu Tongluo decoction alleviates early atherosclerosis of rabbits by inhibiting eNOS uncoupling pathway].

The aim of this paper was to study the curative effect of Huotan Jiedu Tongluo (HTJDTL) decoction on a rabbit model with early atherosclerosis (AS),and furtherly to explore whether it could inhibit the BH4/eNOS uncoupling ROS or not. Twenty-four Japanese white rabbits were randomly divided into sham operation group, model group, HTJDTL decoction group and atorvastatin group. Rabbit models with early atherosclerosis were established by high fat diet, nitrogen drying and carotid artery balloon injury. The rabbits were sacrificed at 7th days after balloon injury and several parameters were measured. The pathological morphology of the common carotid artery was observed by HE staining. The blood lipids were detected by peroxidase method. The ratio of vascular eNOS dimer and monomer was measured by Western blot. The ELISA and biochemical technology were respectively used for testing BH4 and ROS levels in serum. The results showed that compared with the sham operation group, the model group had mild stenosis of the common carotid artery lumen, uneven intimal hyperplasia, lipid deposition in the intima and media, and obvious hyperplasia of the adventitia with inflammatory cell infiltration. The HTJDTL decoction could significantly inhibit the intimal hyperplasia compared with the model group, meanwhile, reduce the lipid deposition of the media and the infiltration of the adventitial cells. Compared with the sham operation group, the blood lipids and ROS of the model animals significantly increased, but BH4 and the ratio of eNOS dimer/monomer decreased. Compared with the model group, HTJDTL decoction significantly reduced the TC, ox-LDL and ROS levels, and also up-regulated eNOS dimer/monomer ratio, but it increased BH4 trend without statistical difference. According to the results, it was found that HTJDTL decoction couldsignificantly prevent and improve the vascular remodeling of rabbits model with early atherosclerosis. The mechanism of decoction may largely be related to the inhibition of BH4/eNOS uncoupling and the reduction of oxidative stress.