Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress.

OBJECTIVE: To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway. METHODS: A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg·d)], and the captopril group [2.25 mg/(kg·d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (-dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis. RESULTS: QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, -dp/dt max, and decreased LVEDP (P<0.05, P<0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P<0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/IRE1 ratio (P<0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P<0.05, P<0.01). CONCLUSION: The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.

Effectiveness and pharmacological mechanisms of Chinese herbal medicine for coronary heart disease complicated with heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) is widely used for treating coronary heart disease complicated with heart failure (CHD-HF). However, the exact mechanisms involved are still not fully understood. AIM OF THE STUDY: To assess the clinical effectiveness and potential pharmacological mechanisms of CHM for treating CHD-HF. METHODS: Eight databases were retrieved for Randomized Controlled Trials of CHM for CHD-HF published from their inception to March 2023. Quality assessment of include studies was performed by the Cochrane risk-of-bias. Meta-analysis was used to assess the effectiveness of CHM for CHD-HF, and then core drugs and active ingredients were selected by data mining and network pharmacology. Finally, cluster and enrichment analysis were adopted to explore the potential targets and signaling pathways. RESULTS: A total of 52 studies enrolling 5216 patients were included. Meta-analysis revealed that CHM treatment groups significantly improved left ventricular ejection fraction (LVEF), 6-min walk test (6-MWT), left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic diameter (LVESD) than control groups: [LVEF: SMD = 0.7, 95%CI (0.54, 0.87), p < 0.00001, I2 = 80%; 6-MWT: SMD = 0.72, 95%CI (0.58, 0.86), p < 0.0001, I2 = 67%; LVEDD: SMD = -0.79, 95%CI (-0.89, -0.69), p < 0.0001, I2 = 49%; LVESD: SMD = -0.6 (-0.74, -0.46), p < 0.0001, I2 = 0%]. The results of various biological information analysis showed the internal relationship between prescriptions, core drugs, active ingredients and therapeutic targets. Twelve core herbs with the most commonly use and high correlation were selected from 110 CHMs of 52 prescriptions for CHD-HF treatment, and further 65 effective components were screened out according to the most strength value, which were divided into 12 compounds such as terpenoids, flavonoids, steroids and alkaloids and etc. At the same time, 67 therapeutic targets of active ingredients in CHD-HF were filtrated. On these bases, cluster and enrichment analysis of the components and targets were used to explore relevant pharmacological mechanisms, mainly including anti-myocardial cell damage, anti-inflammation, anti-apoptosis, anti-fibrosis, regulation of oxidative stress, anticoagulation and angiogenesis, and improvement of glucose and fatty acid metabolism. CONCLUSION: CHM are effective in treating CHD-HF compared with conventional treatment. Some of the included studies have high risks in the implementation of blinding, so more high-quality studies are needed. The active ingredients of CHM could protect the myocardium and improve pathological environment of CHD-HF in various ways. And CHM has the advantage of multi-component and multi-target treatment for complex diseases.

Effect of WenXin KeLi on Improvement of Arrhythmia after Myocardial Infarction by Intervening PI3K-AKT-mTOR Autophagy Pathway.

Background: Myocardial infarction (MI) is an acute and serious cardiovascular disease. Arrhythmia after MI can lead to sudden cardiac death, which seriously affects the survival outcome of patients. WenXin KeLi is a Chinese patent medicine for the treatment of arrhythmia in a clinic, which can significantly improve symptoms of palpitation and play an important role in reducing the risk of arrhythmia after MI. In this study, we aimed to explore the pharmacological mechanism of WenXin KeLi in protecting the heart. Methods: The MI model was established by ligating the left coronary artery and the ventricular fibrillation threshold (VFT) was measured by electrical stimulation. The expression of connexin43 (CX43) and autophagy-related protein were measured by Western Blot, and correlation analysis was conducted to study the relationship between cardiac autophagy, CX43, and arrhythmia in rats after MI. The effects of WenXin KeLi on arrhythmia, cardiac structure, and function in MI rats were respectively observed by electrical stimulation, cardiac gross section, Masson staining, and cardiac ultrasound. The effects of WenXin KeLi on the expression of phosphoinositide 3 kinase-protein kinase B-mammalian targets of rapamycin (PI3K-AKT-mTOR) autophagy pathway and CX43 were observed by Western Blot. Results: After 4 weeks of MI, the VFT in the model group was significantly reduced, the expression levels of yeast ATG6 homolog (Beclin1), microtubule-associated protein 1A/1B-light chain 3 (LC3II/LC3I), and p-CX43 (S368) significantly increased, the expression of sequestosome-1(P62) and CX43 significantly decreased. LC3II/LC3I and Beclin1 expression were significantly negatively correlated with the VFT, and the expression of P62 and CX43 were significantly positively correlated with the VFT. LC3II/LC3I and Beclin1 expression were negatively correlated with CX43 expression, while P62 expression was positively correlated with CX43 expression. WenXin KeLi could significantly increase the VFT, reduce the deposition of collagen fibers, and increase the index levels of the left ventricular end-diastolic anterior wall (LVEDAW), interventricular septum end-diastolic (IVSED), left ventricular end-systolic anterior wall (LVESAW), interventricular septum end-systolic (IVSES), left ventricular end-diastolic posterior wall (LVEDPW), left ventricular end-systolic posterior wall (LVESPW), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduce the index levels of the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). WenXin KeLi could increase the expression of CX43, P62, AKT, p-PI3K, p-AKT (308), p-AKT (473), and p-mTOR and decrease the expression of LC3II/LC3I and Beclin1. Conclusion: WenXin KeLi can activate the PI3K-AKT-mTOR signaling pathway, improve cardiac autophagy and Cx43 expression in rats after MI, reduce the risk of arrhythmia after MI, and play a cardioprotective role.

Evidence and Characteristics of Traditional Chinese Medicine for Coronary Heart Disease Patients With Anxiety or Depression: A Meta-Analysis and Systematic Review.

Aims: The objective of this study was to assess the efficacy and potential mechanisms of Chinese herbal medicine (CHM) for treating coronary heart disease (CHD) patients with anxiety or depression. Methods: A systematic literature search was performed. Screening studies, extracting data, and assessing article quality were carried out independently by two researchers. The active ingredients of CHM for the treatment of CHD with anxiety or depression were analyzed by the network pharmacology, and the main potential mechanisms were summarized by the database of Web of Science. Results: A total of 32 studies were included. The results showed that compared with the blank control groups, CHM was more beneficial in treating anxiety or depression in patients with CHD [anxiety: OR = 3.22, 95% CI (1.94, 5.35), p < 0.00001, I2 = 0%; depression: OR = 3.27, 95% CI (1.67, 6.40), p = 0.0005, I2 = 0%], and the efficacy of CHM was not inferior to that of Western medicine (WM) [anxiety: OR = 1.58, 95%CI (0.39, 6.35), p = 0.52, I2 = 67%; depression: OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I2 = 33%,]. Additionally, CHM also showed a significant advantage in improving angina stability (AS) in CHD patients with anxiety or depression compared with blank groups [anxiety: SMD = 0.55, 95%CI (0.32, 0.79), p < 0.00001, I2 = 0%; depression: p = 0.004] and WM groups [anxiety: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I2 = 0%; depression: SMD = 12.15, 95%CI (6.07, 18.23), p < 0.0001, I2 = 0%]. Angina frequency (AF) and electrocardiogram (ECG) analysis after using CHM demonstrated similar trends. Based on the network pharmacology, quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, stigmasterol, isorhamnetin, baicalein, tanshinone IIa, and nobiletin were most closely and simultaneously related to the pathological targets of CHD, anxiety, and depression. The main underlying mechanisms might involve anti-damage/apoptosis, anti-inflammation, antioxidative stress, and maintaining neurotransmitter homeostasis. Conclusion: CHM exhibited an obvious efficacy in treating CHD patients with anxiety or depression, especially for improving the symptom of angina pectoris. The most active compounds of CHM could simultaneously act on the pathological targets of CHD, anxiety, and depression. Multiple effective components and multiple targets were the advantages of CHM compared with WM.

The Improvement of Cardiac and Endothelial Functions of Xue-Fu-Zhu-Yu Decoction for Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Xue-Fu-Zhu-Yu decoction (XFZYD) is a traditional Chinese prescription that has been used to treat patients with blood stasis in China for many years. The present study aimed to evaluate the improvement of cardiac and endothelial functions of XFZYD for patients with acute coronary syndrome (ACS) through a systematic review and meta-analysis. METHODS: Six databases were searched to collect RCTs related to the treatment of XFZYD for ACS. The primary outcomes were cardiac and endothelial functions, including the levels of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) in echocardiography, as well as the changes in the levels of nitric oxide (NO), endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in the serum. The secondary outcomes were the blood levels of oxidative damage markers (including superoxide dismutase (SOD) and malondialdehyde (MDA)), C-reactive protein (CRP), brain natriuretic peptide (BNP), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) as well as the incidence of adverse drug reactions (ADRs). Weighted mean difference (WMD) was estimated for all the outcomes with the random effects model. This type of analysis was conducted in the subgroups of the ACS subtypes, and the methodological quality was assessed using the handbook of Cochrane Collaboration. RESULTS: A total of 1,658 records were identified, and 16 randomized controlled trials (1,171 patients) were included. The primary outcomes suggested that XFZYD combined with routine treatment improved LVEF, reduced LVEDD and LVESD, and also improved the serum levels of NO, and reduced the levels of ET-1 and ICAM-1. XFZYD combination therapy significantly ameliorated the blood levels of SOD, MDA, BNP, CK-MB, and cTnI. However, the results indicated no significant difference between XFZYD plus routine treatment and routine treatment for the levels of VCAM-1 and CRP. Moreover, all the ADRs reported in the included studies were slight and the patients recovered soon. CONCLUSIONS: The present study suggested that XFZYD may improve the cardiac and endothelial functions of ACS patients without serious ADRs. However, based on the mediocre methodological quality, the aforementioned conclusion should be confirmed in a multicenter, large-scale, and accurately designed clinical trial.

Atheroprotective Effects and Mechanisms of Postmarketing Chinese Patent Formulas in Atherosclerosis Models: A Systematic Review.

BACKGROUND: Some postmarketing Chinese patent formulas have been widely used to treat atherosclerosis (AS) and play critical roles in Chinese healthcare. However, the usage of these herbs is yet controversial due to unclear effects and lack of understanding of the mechanism of action. With the modernization of traditional Chinese formulas, we are to elucidate the atheroprotective properties of these remedies from successful postmarketing experiments in vivo. METHODS: In this systematic review, we critically searched the databases, applied stringent criteria, assessed the methodological quality, and examined the current evidence in vivo. RESULTS: Consequently, 60 studies were included in the present qualitative synthesis. Data on models, high-fat diet, intervention time, outcome measures, efficacy, and mechanisms were collected. Finally, 23 formulas that could alleviate AS were correlated to the amelioration of plaques, improvement of plaque stability, modification of lipid level and lipid metabolism, and the effects of anti-inflammation and antioxidant stress with multiple components and targets. However, the methodological quality was low and incomplete among the included literature. CONCLUSIONS: Thus, taken together, the studies on postmarketing Chinese patent formulas would provide a novel approach to improve the treatment of AS, and rigorously designed studies would provide high-quality evidence.

Wenxin Granules Regulate Endoplasmic Reticulum Stress Unfolded Protein Response and Improve Ventricular Remodeling on Rats with Myocardial Infarction.

Background. Arrhythmia after myocardial infarction is the leading cause of death in clinical heart disease. Increasing studies have shown that the response to endoplasmic reticulum (ER) stress (ERS) caused by myocardial infarction is related to prognosis and the development of arrhythmias. The unfolded protein response (UPR) could serve as an important regulatory signaling pathway following myocardial infarction. The traditional Chinese medicine Wenxin Granules improve arrhythmias following myocardial infarction, which may be related to ERS intervention and the activation of the UPR and apoptosis. We aimed to investigate the involvement of Wenxin Granules in the activation of the UPR and apoptosis following myocardial infarction. Left coronary artery ligation was established as a rat model of myocardial infarction. The rats were randomly divided into the model group, low-dose Wenxin Granule group, high-dose Wenxin Granule group, and metoprolol group. Rats with only wire insertion and no ligature were used as the sham group. Small animal ultrasound systems were used to detect changes in heart structure and function, and the electrical stimulation threshold for ventricular fibrillation was detected. The expression of glucose-regulated protein (GRP)78, activating transcription factor (ATF)6, X-box binding protein (XBP)1, protein kinase-like ER kinase (PERK), phosphorylated (p)-PERK, Bax, Bcl2, C/EBP homologous protein (CHOP), caspase 12, caspase 8, and caspase 3 were detected by western blot, and terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) was used to determine the cardiomyocyte apoptosis index. Compared with the sham group, rats in the model group displayed immediate ST-segment elevation and pathological Q waves after 24 hours. After 2 weeks, the left ventricular (LV) anterior wall thickness (LVAW) became thinner, and the inner diameter (LVID) increased. The end-diastolic LVAW (LVAWd), end-systolic LVAW (LVAWs), ejection fraction (EF), and fractional shortening (FS) were significantly reduced (P < 0.01), whereas the LVIDd, LVIDs, diastolic LV volume (LV Vold), and systolic LV volume (LV Vols) significantly increased (P < 0.01). The ventricular fibrillation threshold decreased significantly (P < 0.01). ERS proteins GRP78, p-PERK, PERK, ATF6, and XBP1 and apoptotic proteins CHOP, Bax, caspase 12, caspase 8, and caspase 3 significantly increased (P < 0.01, P < 0.05), whereas Bcl-2 expression and the Bcl-2/Bax ratio decreased (P < 0.01). Compared with the sham group, LVAWd, LVAWs, FS, and Bcl-2 protein expression were significantly increased in the low-dose Wenxin Granule group (P < 0.01, P < 0.05), and p-PERK and ATF6 decreased (P < 0.01, P < 0.05). Compared with the sham group, LVAWd, LVAWs, EF, FS, and the ventricular fibrillation threshold significantly increased in the high-dose Wenxin Granule and metoprolol groups (P < 0.01, P < 0.05), whereas LVIDs, LV Vols, and ERS proteins were significantly decreased (P < 0.01, P < 0.05). CHOP, Bax, caspase 12, caspase 8, and caspase 3 protein expression decreased in the Wenxin Granule group (P < 0.01, P < 0.05), whereas Bcl-2 and the Bcl-2/Bax ratio increased (P < 0.01, P < 0.05). LVIDd and Bax decreased in the metoprolol group (P < 0.01, P < 0.05), and the Bcl-2/Bax ratio increased (P < 0.05). The cardiomyocyte apoptosis index values for the low- and high-dose Wenxin Granule and metoprolol groups were significantly reduced (P < 0.05). This study suggested that the UPR is an essential mechanism underlying pathological injury after myocardial infarction. Wenxin Granule treatment can improve ventricular remodeling and cardiac function and inhibit arrhythmia by preventing excessive ERS from activating the UPR and apoptosis.

Advances of Traditional Chinese Medicine Regulating Connexin43 in the Prevention and Treatment of Myocardial Infarction.

Gap junctions are the main form of interaction between cardiomyocytes, through which the electrochemical activities between cardiomyocytes can be synchronized to maintain the normal function of the heart. Connexins are the basis of gap junctions. Changes in the expression, structural changes (e.g., phosphorylation and dephosphorylation), and distribution of connexins can affect the normal electrophysiological activities of the heart. Myocardial infarction (MI) and concurrent arrhythmia, shock, or heart failure can endanger life. The structural and functional damage of connexin (Cx) 43 in cardiomyocytes is a central part of the pathological progression of MI and is one of the main pathological mechanisms of arrhythmia after MI. Therefore, increasing Cx43 expression has become one of the main measures to prevent MI. Also, intervention in Cx43 expression can improve the structural and electrical remodeling of the myocardium to improve MI prognosis. Here, research progress of Cx43 in MI and its prevention and treatment using Traditional Chinese Medicine formulations is reviewed.

Guanxinshutong Alleviates Atherosclerosis by Suppressing Oxidative Stress and Proinflammation in ApoE-/- Mice.

Atherosclerosis (AS) is a chronic progressive disease related to dyslipidemia, inflammation, and oxidative stress. Guanxinshutong capsule (GXST), a traditional Chinese medicine, has been widely used in treating coronary atherosclerotic heart disease, while its mechanism actions on AS are still not to be well addressed. Our present study is aimed to examine the effect of GXST on AS and elucidate the multitarget mechanisms of GXST on AS. Network pharmacology analysis was employed to screen the multitarget mechanisms of GXST on AS. ApoE-/- mice were used to validate these effects. Circulating lipid profile and oxidative stress-related factors were measured by the Elisa kit. Furthermore, the aortic trunk and aortic root were excised for oil red O staining, histopathological and immunohistochemical analysis. We first discovered that GXST was clued to exert synergistically antiatherosclerosis properties including lipid-lowering, anti-inflammation, and antioxidation through the computational prediction based on a network pharmacology simulation. Next, the validation experiments in atherosclerosis mice provided evidence that GXST significantly reduced atherosclerotic lesions, increased collagen deposition, and attenuated LV remodeling to some extent. Mechanistically, GXST modulated lipid profile, downregulated the level of inflammatory cytokines and NF-κBp65. GXST also reduced the activity of oxidative parameter MDA and upregulated the activities of antioxidant enzymes (SOD and GSH) compared with the AS model group. In conclusion, GXST intervention might attenuate atherosclerosis by mechanisms involving reducing lipid deposition, modulating oxidative stress and inflammatory responses, but a larger controlled trial is necessary for confirmation.

Qiliqiangxin prevents right ventricular remodeling by inhibiting apoptosis and improving metabolism reprogramming with pulmonary arterial hypertension.

Pathological remodeling of the right ventricular (RV) contributes to the mortality of pulmonary arterial hypertension (PAH) patients, and RV myocardial apoptosis and metabolism play decisive roles in RV remodeling. Qiliqiangxin (QLQX), a traditional Chinese medicine, has a cardio-protective effective on left ventricular remodeling. However, whether QLQX can decrease RV myocardial apoptosis, improve metabolism, and attenuate RV remodeling remain uncertain. This study investigated the effects of QLQX on RV remodeling, myocardial mitochondria, apoptosis, and metabolism reprogramming. RV remodeling was induced by intraperitoneal injection of Monocrotaline (MCT). We first discovered that QLQX improved hemodynamic parameters and inhibited MCT-induced RVH. Next, QLQX significantly attenuated RV remodeling which covered RV myocardial fibrosis, and RV capillary density. Furthermore, we uncovered that QLQX attenuated RV myocardial apoptosis. We also confirmed that QLQX reversed metabolic shift toward glycolysis which decreased the uptake of glucose showed by fluorodeoxyglucose F 18 positron emission tomography (18FDG-PET). Mechanistically, QLQX optimized mitochondrial function by ameliorating structural abnormality of mitochondria, reducing the release of cytochrome c from mitochondria, and upregulating the expression of SOD2. Mitochondria-dependent apoptosis and mitochondria-associated metabolism were involved in QLQX regulation of RV. Moreover, our study showed that PINK1/Parkin 2 pathway was involved in improving mitochondrial function. We concluded that QLQX could inhibit PAH-induced RV remodeling by decreasing mitochondria associated apoptotic pathway and reversing mitochondrial related metabolic shift. The PINK1/Parkin mitophagy pathway may play a key role in mitochondria protection.

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.

Qiliqiangxin Capsule Improves Cardiac Function and Attenuates Cardiac Remodeling by Upregulating miR-133a after Myocardial Infarction in Rats.

Qiliqiangxin capsule (QLC), a natural herb recipe with therapeutic effect from China, has been widely used in clinical practice for attenuating cardiac remodeling induced by myocardial infarction (MI). However, the pharmacological mechanism of QLC on cardiac remodeling after MI is not entirely clear. The present study aims to investigate the effectiveness and mechanisms of QLC on cardiac remodeling induced by MI in rats. The animal model was established by permanently ligating the left anterior descending coronary artery in rats. Subsequently, rats with successful ligation were randomly divided into model group, captopril group, and QLC group. And the control group was operated upon in parallel except ligation, namely, the sham group. All rats were treated through the intragastric administration once a day for 4 weeks. Cardiac hemodynamics was measured after treatment. Then, the left ventricular mass index (LVMI) was examined. The pathological changes were observed by HE staining. The collagen volume fraction (CVF) was detected by Masson trichrome staining. The apoptosis index was obtained by TUNEL fluorescent staining. The miR-133a and mRNA of TGF-ß1, CTGF, Caspase9, and Caspase3 were examined by real-time PCR. The protein expressions of TGF-ß1, CTGF, Caspase9, Caspase3, and cleaved-Caspase3 were tested by Western blot. Compared with the model group, QLC partially improved cardiac hemodynamics and decreased LVMI. miR-133a was significantly increased in QLC group. In addition, QLC declined CVF by downregulating TGF-ß1 rather than CTGF. Meanwhile, QLC decreased the apoptosis index by attenuating Caspase9, Caspase3, and cleaved-Caspase3. This study suggested that QLC could improve cardiac function and partially attenuate cardiac remodeling by attenuating fibrosis and decreasing apoptosis, which might be partially related to miR-133a, TGF-ß1, Caspase9, and Caspase3.

Effectiveness and safety of Xuefu Zhuyu decoction for treating coronary heart disease angina: A systematic review and meta-analysis.

BACKGROUND: Coronary heart disease angina is a very common cardiovascular disease, which not only causes personal health problems, but also a serious burden on the social economy. Xuefu Zhuyu Decoction (XFZYD) has been widely adapted to clinical practice for people with coronary heart disease angina. At present, it is necessary to update the existing research, re-evaluate the effectiveness and safety of XFZYD, and provide the latest evidence for coronary heart disease angina. METHODS AND ANALYSIS: The purpose of this study was to search the electronic database for XFZYD in the treatment of coronary heart disease angina. The database includes PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure database (CNKI), Wanfang database, Chinese Biomedical Literature database (CBM), Chinese Scientific Journal database (VIP). In addition, ongoing trials will be retrieved from the WHO ICTRP Search Portal, the Chinese Clinical Trial Register and The Clinical Trials Register. We will assess all the documents from the database establishment to January 31, 2019. The RevMan V.5.3 software will be used to calculate the data synthesis and perform a meta-analysis when the literature is appropriate. RESULTS: The study will provide a high-quality synthesis of current evidence of XFZYD for coronary heart disease angina from the various comprehensive assessment, including Significantly effective, Effective, Invalid, Aggravation, which based on the "Guidelines for Clinical Research of New Chinese Medicine". Adverse events are also included. CONCLUSION: The systematic review will provide evidence for assessing the effectiveness and safety of XFZYD in the treatment of coronary heart disease angina. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019122003.

[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.

Bao Yuan decoction and Tao Hong Si Wu decoction improve lung structural remodeling in a rat model of myocardial infarction: Possible involvement of suppression of inflammation and fibrosis and regulation of the TGF-ß1/Smad3 and NF-κB pathways.

Chronic heart failure (CHF) leads to pulmonary structural remodeling, which may be a key factor for poor clinical outcomes in patients with end-stage heart failure, and few effective therapeutic options are presently available. The aim of the current study was to explore the mechanism of action and pulmonary-protective effects of treatment with Bao Yuan decoction combined with Tao Hong Si Wu decoction (BYTH) on lung structural remodeling in rats with ischemic heart failure. In a model of myocardial infarction (MI) induced by ligation of the left anterior descending (LAD) artery, rats were treated with BYTH. Heart function and morphometry were measured followed by echocardiography, histological staining, and immunohistochemical analysis of lung sections. The levels of transforming growth factor-ß1 (TGF-ß1), type I collagen, phosphorylated-Smad3 (p-Smad3), tumor necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4), active nuclear factor κB (NF-κB) and alpha smooth muscle actin (α-SMA) were detected using Western blotting. Lung weight increased after an infarct with no evidence of pulmonary edema and returned to normal as a result of BYTH. In addition, BYTH treatment reduced levels of type I collagen, TGF-ß1, and α-SMA expression and decreased the phosphorylation of Smad3 in the lungs of rats after MI. BYTH treatment also reduced the elevated levels of lung inflammatory mediators such as TNF-α, TLR4, and NF-κB. Results suggested that BYTH could effectively improve lung structural remodeling after MI because of its anti-inflammatory and anti-fibrotic action, which may be mediated by suppression of the TGF-ß1/Smad3 and NF-κB signaling pathways.

Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-ß1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction.

BACKGROUND/AIMS: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. METHODS: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-ß1 (TGF-ß1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. RESULTS: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-ß1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. CONCLUSIONS: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-ß1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

Effect of Wenxin Granules on Gap Junction and MiR-1 in Rats with Myocardial Infarction.

Myocardial infarction (MI) patients are at high risk of potential lethal arrhythmia. Gap junction and microRNA-1 (miR-1) are both arrhythmia generating conditions. The present study investigated whether Wenxin Granules (Wenxin-Keli, WXKL) could prevent potential lethal arrhythmia by improving gap junctions and miR-1 following MI. Male Sprague-Dawley rats were divided randomly into control, model, metoprolol, low dose WXKL, and high dose WXKL groups. The MI rat model was created by coronary artery ligation. Treatments were administrated intragastrically to the rats for 4 weeks. Conventional transmission electron microscopy was performed to observe the ultrastructure of gap junctions. Quantitative real-time PCR and western blotting were used to detect the expression of miR-1, protein kinase C (PKC), and related proteins. Additionally, a programmatic electrophysiological stimulation test was performed to detect the ventricular fibrillation threshold (VFT). WXKL protected the ultrastructure of the gap junctions and their constituent Cx43 by regulating miR-1 and PKC mediated signal transduction and increased the VFT significantly in the rat MI model. The results suggested that WXKL is an effective alternative medicine to prevent potentially lethal arrhythmia following MI.

miRNA Expression Profile and Effect of Wenxin Granule in Rats with Ligation-Induced Myocardial Infarction.

Wenxin Granule (WXKL) is a traditional Chinese medicine used for treatment of myocardial infarction (MI) and arrhythmias. However, the genomic pathological mechanisms of MI and mechanisms of WXKL are largely unknown. This study aims to investigate a comprehensive miRNA expression profile, and the predicted correlation pathways to be targeted by differentially expressed miRNAs in MI, and mechanisms of WXKL from a gene level. MI rat model was established by a coronary artery ligation surgery. miRNA expression microarrays were performed and the data were deposited in Gene Expression Omnibus (GEO number GSE95855). And, pathway analysis was performed by using the DIANA-miRPath v3.0 online tool. The expressions of miR-1, miR-133, Cx43, and Cx45 were detected by quantitative real-time PCR. It was found that 35 differentially expressed miRNAs and 23 predicted pathways, including miR-1, miR-133, and gap junction pathway, are involved in the pathogenesis of MI. And, WXKL increased the expressions of miR-1 and miR-133, while also increased the mRNA levels of Cx43 and Cx45, and, especially, recovered the Cx43/Cx45 ratio near to normal level. The results suggest that regulatory effects on miR-1, miR-133, Cx43, and Cx45 might be a possible mechanism of WXKL in the treatment of MI at the gene level.

[Effects of Qili Qiangxin Capsule on Lung Structural Remodeling in Heart Failure Rats after Myocardial Infarction and Its Mechanism].

Objective To observe the effect of Qili Qiangxin Capsule (QQC) in improving lung struc- tural remodeling on heart failure (HF) rats after myocardial infarction (Ml) and to study its possible mecha- nism. Methods The proximal left anterior descending branch of coronary artery was ligated using a terylene suture to establish acute myocardial infarction (AMI) rat model. After successful AMI modeling rats were ran- domly divided into the model group (intragastrically administered with distilled water at 1 mL/100 g, n =13) and the QQC group (intragastrically administered with QQC at the daily dose of 1 g/kg, n =9). And the sham-opera- tion group (intragastrically administered with distilled water at 1 mL/100 g, n =10) was also set up. After four weeks intervention heart functions of rats were detected using echocardiography. The pathological changes of lung structures were observed by HE and Masson staining method. Protein expressions of lung α-SMA, Collagen I, TGF-ß1, and p-Smad3 of the lung tissue were detected by immunohistochemistry and Western blot. Re- sults Compared with the sham-operation group, ejection fraction (EF) and fraction shortening (FS) decreased (P <0. 05) , protein expressions of lung left ventricular internal diastolic diameter (LVIDd), left ventric- ular internal systolic diameter (LVIDs), end diastolic volume (EDV), end systolic volume (ESV), α-smooth muscle actin (a-SMA), Collagen I, tumor growth factor-ß1 (TGF-ß1), and p-Smad3 increased (P <0.05) in the model group. The muscularized small arteries ratio and collagen area of the lung tissue increased in the model group (P <0. 05). Compared with the model group, EF and FS increased (P <0. 05), protein expressions of LVIDs, ESV, α-SMA, Collagen I, TGF-ß, , and p-Smad3 decreased (P <0.05) in the QQC group. The muscular- ized small arteries ratio and collagen area of the lung tissue decreased in the QQC group (P <0. 05). Conclusion QQC could improve lung structural remodeling degree of HF rats after MI, and its possible mechanism might be achieved by regulating TGF-beta,/Smad3 signaling pathways.

Yiqihuoxuejiedu Formula Restrains Vascular Remodeling by Reducing the Inflammation Reaction and Cx43 Expression in the Adventitia after Balloon Injury.

Vascular remodeling is closely related to hypertension, atherosclerosis, and restenosis after PCI. Considerable evidence indicates that the activation and proliferation of adventitial fibroblasts play key roles in vessel injury. The inflammatory response and high expression of connexins contribute to adventitial remodeling. Therefore, reducing inflammation reaction and connexins expression in adventitia may become a new target to prevent vascular remodeling. Yiqihuoxuejiedu formula, composed of TCM therapeutic principle of supplementing qi, activating blood and detoxification, can inhibit restenosis after intimal injury. To further investigate the effect of Yiqihuoxuejiedu formula on inflammation and connexins, we established a carotid artery injury model. In model rats, hyperplasia in the intima was mild but obvious in the adventitia; CRP heightened; expressions of MCP-1, CD68, and Cx43 increased. Yiqihuoxuejiedu formula relieved intimal hyperplasia and adventitial area, obviously diminished the expressions of CD68 and Cx43 in the adventitia, and reduced CRP but did not lower MCP-1. These results indicated that Yiqihuoxuejiedu formula inhibited vascular remodeling especially adventitial hyperplasia by reducing the inflammation reaction including lowering macrophages infiltration and systemic nonspecific inflammatory response and also restraining gap junction connexins leading to less communication among cells. This study provides new ideas and methods for the prevention and treatment of vascular remodeling.