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Diabetes mellitus is one of the most prevalent global public health issues associated with a higher risk of cardiovascular diseases, contributing to morbidity and mortality. Research has demonstrated that elevated reactive oxygen species (ROS) generation in diabetes can trigger apoptosis, exacerbating diabetic cardiomyopathy (DCM). This study investigates the cardioprotective effects of Paederia foetida in rats’ models of type 2 diabetes induced by a high-fat diet (HFD) and streptozotocin (STZ) treatment. The diabetic model was established in Sprague Dawley rats by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg). Sprague Dawley rats were treated with varied concentrations of standardized extract of P. foetida (50 mg/kg and 100 mg/kg), administered orally once daily for four weeks. Standardized extract from P. foetida has a range of therapeutic potential, including anti-inflammatory, antioxidant, and anti-diabetic properties. The common metabolic disorder indices and myocardial apoptosis were investigated. The findings from this study demonstrated increased expression of Bcl-2 and decreased expression of Bcl-2 Associated X-protein BAX as indicated by IRS scoring in cardiomyocytes, suggesting that P. foetida has a significant protective effect on diabetic cardiomyopathy by decreasing apoptosis. Increased Bcl-2 and decreased BAX levels may be related to regulating oxidative stress and mitochondrial pathways involving myocardial apoptosis. P. foetida extract could be a potential intervention for attenuating cardiomyopathy in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Gastrodin, a highly potent compound found in the traditional Chinese medicine Gastrodia elata Blume, exhibits significant antihypertensive properties. However, its role and the mechanism behind its protective effects on hypertensive cardiac conditions are not well understood. This study aims to investigate the cardiac protective effects and underlying mechanisms of gastrodin in angiotensin II (Ang II)-induced hypertensive models, both in vivo and in vitro. Treatment with gastrodin significantly decreased blood pressure and the heart weight/tibial length (HW/TL) ratio and attenuated cardiac dysfunction and pathological damage in Ang II-infused C57BL/6 mice. RNA sequencing analysis (RNA-seq) revealed 697 up-regulated and 714 down-regulated transcripts, along with 1105 signaling pathways, in Ang II-infused C57BL/6 mice following gastrodin treatment, compared to Ang II-induced hypertensive mice. Furthermore, the analyses of the top 30 Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway indicated significant enrichment in apoptosis and the peroxiredoxin 2 (PRDX2)/p53 pathway. Consistently, gastrodin treatment significantly reduced myocardial apoptosis in both the cardiac tissues of Ang II-induced hypertensive mice and Ang II-stimulated H9c2 cells. Additionally, gastrodin treatment significantly decreased the protein levels of PRDX2, p53, cleaved caspase-3, cleaved caspase-9, and Bax/Bcl-2 ratio in the cardiac tissues of Ang II-infused mice and H9c2 cells stimulated with Ang II. In conclusion, gastrodin treatment can mitigate hypertension-induced myocardial apoptosis in hypertensive mice by inhibiting the PRDX2/p53 pathway. [ABSTRACT FROM AUTHOR]

Background Erxian decoction (EXD) is an empirical formula for treating cardiovascular disease, our previous work has shown that EXD could improve the cardiovascular structure and function in ovariectomized (OVX) rats, but its pharmacological mechanism is still unclear.Materials and Methods Network pharmacology was utilized to assess the key active components and central targets of EXD in treating postmenopausal cardiovascular disease. Then, an OVX rat model was established, HE staining and transmission electron microscope were utilized to observe myocardial tissue morphology, TUNEL staining was utilized to detect cardiomyocyte apoptosis, western blot, and ELISA were used to confirm efficacy and pathway of EXD.Results The network pharmacology prediction results showed that 129 common targets were identified by intersecting EXD targets and postmenopausal cardiovascular disease targets, including AKT1, TNF, IL-6, IL-1β, PTGS2 and other core targets, apoptosis, PI3K/AKT, and other signaling pathways may be closely related to postmenopausal cardiovascular disease. After ovariectomy, the myocardial tissue of rats was damaged, the expression level of PI3K/AKT pathway-related molecules in the myocardial tissue were decreased, the apoptosis index of cardiomyocytes was increased, and the levels of inflammatory factors (TNF-α, IL-6, and IL-1β) were enhanced. EXD intervention could improve myocardial tissue injury, EXD could up-regulate the protein expression of PI3K and p-AKT in myocardial tissue, and thereby prevent myocardial cell apoptosis. At the same time, EXD downregulated the levels of inflammatory factors in serum of ovariectomized rats.Conclusion EXD may prevent myocardial tissue damage through induction of the PI3K/AKT signaling pathway, thereby reducing cardiomyocyte apoptosis and inflammation. EXD may be a potential drug for the treatment of postmenopausal cardiovascular disease.

The accumulation of the active pharmaceutical chemical in the environment usually results in environmental pollution to increase the risk to human health. Indomethacin is a non-steroidal anti-inflammatory drug that potentially causes systemic and developmental toxicity in various tissues. However, there have been few studies for its potential effects on cardiac development. In this study, we systematically determined the cardiotoxicity of acute indomethacin exposure in zebrafish at different concentrations with morphological, histological, and molecular levels. Specifically, the malformation and dysfunction of cardiac development, including pericardial oedema, abnormal heart rate, the larger distance between the venous sinus and bulbus arteriosus (SV-BA), enlargement of the pericardial area, and aberrant motor capability, were determined after indomethacin exposure. In addition, further investigation indicated that indomethacin exposure results in myocardial apoptosis in a dose-dependent manner in zebrafish at early developmental stage. Mechanistically, our results revealed that indomethacin exposure mainly regulates key cardiac development-related genes, especially genes related to the cardiac muscle contraction-related signaling pathway, in zebrafish embryos. Thus, our findings suggested that acute indomethacin exposure might cause cardiotoxicity by disturbing the cardiac muscle contraction-related signaling pathway and inducing myocardial apoptosis in zebrafish embryos.

Abstract Background Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. Objective We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. Method We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. Results We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. Conclusion Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

Background: Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. Objective: We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. Method: We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. Results: We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. Conclusion: Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF. [ABSTRACT FROM AUTHOR]

Septic cardiomyopathy is associated with mechanisms such as excessive inflammation, oxidative stress, regulation of calcium homeostasis, endothelial dysfunction, mitochondrial dysfunction, and cardiomyocyte death, and there is no effective treatment at present. MOTS-c is a mitochondria-derived peptide (MDP) encoded by mitochondrial DNA (mtDNA) that protects cells from stresses in an AMPK-dependent manner. In the present study, we aim to explore the protective effect of MOTS-c on lipopolysaccharide (LPS)-induced septic cardiomyopathy. LPS is used to establish a model of septic cardiomyopathy. Our results demonstrate that MOTS-c treatment reduces the mRNA levels of inflammatory cytokines ( IL-1β, IL-4, IL-6, and TNFα) in cardiomyocytes and the levels of circulating myocardial injury markers, such as CK-MB and TnT, alleviates cardiomyocyte mitochondrial dysfunction and oxidative stress, reduces cardiomyocyte apoptosis, activates cardioprotection-related signaling pathways, including AMPK, AKT, and ERK, and inhibits the inflammation-related signaling pathways JNK and STAT3. However, treatment with the AMPK pathway inhibitor compound C (CC) abolishes the positive effect of MOTS-c on LPS stress. Collectively, our research suggests that MOTS-c may attenuate myocardial injury in septic cardiomyopathy by activating AMPK and provides a new idea for therapeutic strategies in septic cardiomyopathy.

Background: Reperfusion therapy is the most effective approach to resolve coronary occlusion, but myocardial injury caused by excessive inflammation during myocardial ischemia–reperfusion will also pose a new threat to health. Our prior study revealed the expression pattern of interleukin‐38 (IL‐38) in the peripheral blood serum of patients with ischemic cardiomyopathy and the role of IL‐38 in acute myocardial infarction in mice. However, its role and potential mechanisms in myocardial ischemia/reperfusion injury (MIRI) remain to be determined. Methods and Results: The left anterior descending artery of C57BL/6 mice was transiently ligated to induce the MIRI model. We found that MIRI induced the expression of endogenous IL‐38, which was mainly produced by locally infiltrating macrophages. Overexpression of IL‐38 in C57BL/6 mice attenuated inflammatory injury and decreased myocardial apoptosis after myocardial ischemia–reperfusion. Furthermore, IL‐38 inhibited lipopolysaccharide‐induced macrophage inflammation in vitro. Cardiomyocytes cocultured with the supernatant of IL‐38‐ and troponin I‐treated macrophages showed a lower rate of apoptosis than controls. Conclusions: IL‐38 attenuates MIRI by inhibiting macrophage inflammation. This inhibitory effect may be partially achieved by inhibiting the activation of NOD‐like receptor pyrin domain‐related protein 3 inflammasome, resulting in decreased expression of inflammatory factors and reduced cardiomyocyte apoptosis. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role of PPARγ and underlying mechanisms in myocardial ischemia/reperfusion injury (IRI). IRI was surgically induced in mice and neonatal rat cardiomyocytes (NRCM) were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R). Quantitative genetic analysis and western blotting were performed to assess mRNA and protein levels, respectively, of PPARγ, as well as of different inflammatory, fibrosis, and apoptosis markers in cells and tissues. PPARγ was overexpressed in the heart of mice and NRCMs by viral transfection. Apoptosis and fibrosis were detected by TUNEL and Masson's trichrome staining, respectively. Enzyme-linked immunosorbent assay was performed to detect M1 and M2 macrophage-related inflammatory factors present in mouse sera. PPARγ overexpression significantly inhibited OGD/R- and IRI-induced cardiomyocyte apoptosis and fibrosis in vitro and in vivo. Moreover, PPARγ overexpression inhibited IRI-induced secretion of M1-related proinflammatory factors, whereas it supported the secretion of M2-related anti-inflammatory factors. Notably, these events were found to be mediated by the JAK/STAT pathway. In conclusion, PPARγ regulates macrophage polarization upon IRI via the JAK/STAT pathway, which will in turn prevent myocardial apoptosis and fibrosis. Hence, PPARγ may represent a valuable target for myocardial IRI treatment. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is an important factor inducing mortality globally. Apoptosis and oxidative stress have been identified as major drivers for MI development. Anti-apoptosis therapies exhibit promising effects in protecting against MI. Typically, Taohong Siwu Decoction (THSWD) exerts cardioprotective properties. However, whether THSWD suppresses oxidative stress-induced myocardial apoptosis after MI and the associated mechanisms remain unclear. The present work focused on examining the protective effects of THSWD on oxidative stress-induced myocardial apoptosis after MI and its possible mechanisms. The MI mouse model was established via left anterior descending coronary artery (LAD) ligation. Thereafter, echocardiography and histopathology were performed to examine the cardioprotective effects of THSWD. Meanwhile, the protective potential of THSWD against myocardial apoptosis and oxidative stress, as well as modulation of phosphatase and tensin homolog (PTEN) pathway in MI were investigated through TUNEL staining, ROS analysis, immunohistochemistry (IHC), Western blot (WB) and oxidative stress-related biochemical enzyme assay, respectively. Further, the apoptosis of neonatal cardiomyocytes (NCMs) and H9C2 cells was induced by TBHP in vitro. Thereafter, the impacts of THSWD on the TBHP-induced H9C2 and NCMs were detected by Hoechst33342/PI fluorescent staining, WB, ROS analysis, and oxidative stress-related biochemical enzyme assay. In addition, PTEN was overexpressed using transfection viruses in vivo and in vitro for further investigation. THSWD might inhibit PTEN and promote the PI3K/AKT pathway in MI mice to prevent myocardial apoptosis. In vitro , THSWD prevented the TBHP-induced apoptosis of NCMs and H9C2 cells. This was achieved by blocking PTEN activity and regulating PI3K/AKT pathway. Moreover, PTEN overexpression significantly enhanced the TBHP-induced H9C2 apoptosis and oxidative stress-induced myocardial apoptosis after MI, and partially blocked the protection of THSWD against myocardial apoptosis and modulating PI3K/AKT pathway in vitro and in vivo. THSWD suppressed oxidative stress-induced myocardial apoptosis in vitro and in vivo by inhibiting PTEN pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the increased secretion of serpinE1 induced by diabetes can cause nuclear translocation and apoptosis of NF-kB in cardiomyocytes. 8-week-old C57BL/6J mice were randomly divided into control and diabetic group. The diabetes model was induced by intraperitoneal injection of streptozotocin. In vitro, rat myocardial H9C2 cells were treated with low-glucose (5.5 mmol/L) and high-glucose (25 mmol/L) concentration media, respectively. SerpinE1 levels in mouse serum and cell culture supernatant were detected by ELISA, as well as caspase-3 and cleaved caspase-3, in line with NF-kB protein expressions in cytoplasm and nucleus in heart tissue and cells were detected by Western Blot, respectively. In addition, H9C2 cells were divided into three groups: control, serpinE1 recombinant protein, and JSH-23 combined with serpinE1 recombinant protein. Western Blot were used to detect the same indicators above. SerpinE1 levels in serum of diabetic mice and cell culture supernatants treated with high glucose were significantly higher than those in control group (P<0.05). Compared with the control group, nuclear/cytoplasmic NF-kB, cleaved caspase-3/caspase-3 were significantly increased in the myocardial tissue of diabetic mice and H9C2 cells treated with high glucose (P<0.05). Moreover, the nuclear/cytoplasmic NF-kB and cleaved caspase-3/caspase-3 were significantly increased after serpinE1 recombinant protein treatment compared with the control group (P<0.05), while JSH-23 treatment attenuated these effects of serpinE1.Conclusion: Diabetes-induced increase in serpinE1 secretion promotes NF-资B nuclear translocation and apoptosis in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Objectives: To elucidate the regulatory effect of exosomes secreted by bone marrow mesenchymal stem cells (BMSCs-exosomes) on cardiomyocyte apoptosis through miRNA-let-7i-5p in myocardial infarction., Methods: BMSCs-exosomes were extracted, and their morphology and size distribution were analyzed using transmission electron microscope. Expression of exosome surface markers was determined by western blot. H9C2 cells were randomly assigned into five groups, namely control, OGD, OGD+exos, OGD+exos+miR-let-7i-5p inhibitor and OGD+exos+miR-let-7i-5p inhibitor NC. Hypoxic cardiomyocytes were induced using glucose-free Dulbecco's Modified Eagle Medium (DMEM). Mice were randomly assigned into sham, myocardial infarction (MI), MI+exos, MI+exos+miR-let-7i-5p inhibitor and MI+exos+miR-let-7i-5p inhibitor NC groups. MI model was established by ligation of the left anterior descending (LAD) coronary artery. Subsequently, BMSCs-exosomes or BMSCs-exosomes transfected with miRNA-let-7i-5p inhibitor were incubated with hypoxia cardiomyocytes or injected into the MI mouse model. Cell survival was accessed by CCK-8 assay. Cardiomyocyte apoptosis was accessed with V-FITC/PI and TUNEL. Heart function of MI mice was evaluated by echocardiography. Myocardial infarct size was calculated through TTC staining. Relative miRNA-let-7i-5p expression level was determined by RT-qPCR. Expression of apoptosis-related proteins in myocardial tissue were detected by western blot., Results: Exosomes secreted from BMSCs were successfully extracted. In H9C2 cells, miRNA-let-7i-5p expression was significantly upregulated, cell survival rate was increased, and the apoptosis rate was decreased after incubation with BMSCs-exosomes. In MI mice, injection of BMSCs-exosomes markedly upregulated miRNA-let-7i-5p level, reduced infarct size, improved cardiac function, and decreased apoptotic rate. BMSCs-exosomes treatment downregulated Bax and upregulated Bcl-2 protein expression. These effects were reversed by transfection with the miRNA-let-7i-5p inhibitor., Conclusions: BMSCs-exosomes inhibit myocardial apoptosis, attenuate MI progression, and protect against myocardial infarction both in vivo and in vitro through miRNA-let-7i-5p., Competing Interests: None., (AJTR Copyright © 2024.)

IntroductionChronic heart failure (CHF) has become an increasing concern with the aging of the population. This study aims to evaluate the effectiveness and safety of Qili Qiangxin capsules (QLQX) for CHF.MethodsA systematic review and meta-analysis on clinical studies was conducted. The mechanisms of preclinical studies were summarized.ResultsWe searched six electronic databases by 20 July 2022, and finally, 7 preclinical experiments (PEs) and 24 randomized controlled trials were included. The risk of bias was accessed by the SYRCLE and RoB 2.0 tool, respectively. PEs indicated that QLQX suppresses myocardial apoptosis, inhibits renin-angiotensin-aldosterone system activation, improves water retention, and enhances cardiocyte remodeling. In clinical studies, compared with routine treatment, QLQX could improve the indicators: clinical efficacy rate (RR = 1.16, 95% CI [1.12, 1.22], GRADE: moderate), left ventricular end-diastolic dimension (SMD = −1.04, 95% CI [−1.39, −0.70], GRADE: low), left ventricular ejection fraction (SMD = 1.20, 95% CI [0.97, 1.43], GRADE: moderate), 6-minute walk distance (SMD = 1.55, 95% CI [0.89, 2.21], GRADE: low), brain natriuretic peptide (SMD = −0.78, 95% CI [−1.06, −0.51], GRADE: low), N-terminal pro-brain natriuretic peptide (SMD = −2.15, 95% CI [−3.60, −0.71], GRADE: low), and adverse events (RR = 0.46, 95% CI [0.25, 0.87], GRADE: low).DiscussionIn summary, QLQX exerts a potential mechanism of utility on myocardial apoptosis and cardiac function and has noteworthy clinical adjuvant efficacy and safety in patients with CHF.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/.

Endoplasmic reticulum stress (ER stress) is involved in the development and progression of various forms of heart disease and may lead to myocardial apoptosis. Sphingosine-1-phosphate (S1P) possesses cardioprotective properties, including anti-apoptosis. However, little is known about the link between S1P and ER stress-induced myocardial apoptosis. This study investigated the regulatory role of S1P in ER stress-induced apoptosis in cardiomyocytes. ER stress and myocardial apoptosis were induced by transverse aortic constriction (TAC) or tunicamycin in mice, which were then treated with 2-acetyl-5-tetrahydroxybutyl imidazole (THI) or S1P. AC16 cells were treated with tunicamycin or thapsigargin, or pretreated with S1P, sphingosine-1-phosphate receptor (S1PR) subtype antagonists, S1PR1 agonist, and PI3K and MEK inhibitors. Cardiac function, the level of S1P in plasma and heart, ER stress markers, cell viability, and apoptosis were detected. S1P reduced the expression of ER stress-related molecules and ER stress-induced myocardial apoptosis in mice subjected to TAC or an injection of tunicamycin. Furthermore, in AC16 cells exposed to thapsigargin or tunicamycin, S1P decreased the expression of ER stress-related molecules, promoting cell viability and survival. Nevertheless, the S1PR1 antagonist abrogated the protection of S1P. Subsequently, in TAC S1PR1 heterozygous (S1PR1+/–) mice, S1P had no effect on ER stress and apoptosis in cardiomyocytes. Notably, in vitro , the impact of anti-ER stress-induced myocardial apoptosis by the S1PR1 agonist was reversed by PI3K and MEK inhibitors. This study is the first to demonstrate that S1P relieves ER stress-induced myocardial apoptosis via S1PR1/AKT and S1PR1/ERK1/2, which are potential therapeutic targets for heart disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Dapagliflozin (DAPA) exerts cardioprotective effects in non-diabetic patients. Nonetheless, the protective mechanism remains unknown. This study aims to evaluate the performance of DAPA on cardiac function and remodeling as well as its potential mechanism in mice with myocardial infarction (MI). Here, a MI mice model was established. One week after MI, mice were treated with saline or DAPA (1.5 mg/kg/day) for 4 weeks. At the end of this study, echocardiography was performed to assess cardiac structure and function. Myocardial apoptosis was analyzed by Western blot and immunofluorescence. Inflammatory cytokines and cardiac fibrosis were analyzed by real-time PCR and Masson's trichrome stain, respectively. Results showed that DAPA improved cardiac structure and function, attenuated cardiac fibrosis, and inhibited inflammatory cytokines and myocardial apoptosis. Moreover, the inhibition of PI3K/AKT/mTOR pathway might be related to the cardioprotective role of DAPA. These findings reveal that dapagliflozin is a potential therapeutic agent for MI patients without diabetes. [ABSTRACT FROM AUTHOR]

Tao Li, Zhiqing Chen, You Zhou, Haoliang Li, Jian Xie, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning, People’s Republic of ChinaCorrespondence: Lang LiDepartment of Cardiology, The First Affiliated Hospital of Guangxi Medical University & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, 6 Shuangyong Road, Nanning, 530021, Guangxi, People’s Republic of ChinaTel/Fax +86-771-5331171Email drlilang1968@126.comPurpose: Coronary microembolization (CME) is associated with progressive cardiac dysfunction, myocardial inflammation, and apoptosis. Resveratrol (RES) has a considerable role in cardioprotection. However, the contribution and possible mechanisms of RES in CME have not been clearly understood.Methods: In the current study, 40 SD rats were randomly selected and categorized into various groups including CME, CME + resveratrol (CME + RES), CME + resveratrol+ LY294002 (CME + RES + LY), and sham groups (10 animals in each group). The inert plastic microspheres (42 μm) were injected into the rats’ left ventricle for developing the CME model. Then resveratrol (25 mg/kg/d) was given to the rats in the CME + RES and CME + RES + LY groups for one week before CME induction. Furthermore, LY294002 (10 mg/kg) was intraperitoneally injected into the rats of the CME + RES + LY group 0.5 hours before CME modeling. The cardiac functions, serum levels of myocardial injury biomarkers, myocardial histopathology, and mRNA and proteins associated with myocardial apoptosis were all assessed 12 hours after surgery.Results: The results revealed that resveratrol pretreatment alleviated the CME-induced myocardial damage by improving cardiac dysfunction, and lowering the serum level of myocardial injury biomarkers, myocardial microinfarct size, and cardiomyocyte apoptotic index. Pretreatment with resveratrol reduced the level of proteins and mRNAs associated with the pro-apoptosis in myocardial tissues and increased the levels of proteins and mRNAs associated with the anti-apoptosis. Moreover, the combined treatment of resveratrol and LY294002 reversed the observed protective effects.Conclusion: Resveratrol can inhibit cardiomyocyte apoptosis, thus attenuating the CME-induced myocardial injury by triggering the PI3K/Akt/GSK-3β cascade.Keywords: resveratrol, myocardial apoptosis, PI3K/Akt/GSK-3β, coronary microembolization, cardiac dysfunction

The accumulation of the active pharmaceutical chemical in the environment usually results in environmental pollution to increase the risk to human health. Indomethacin is a non-steroidal anti-inflammatory drug that potentially causes systemic and developmental toxicity in various tissues. However, there have been few studies for its potential effects on cardiac development. In this study, we systematically determined the cardiotoxicity of acute indomethacin exposure in zebrafish at different concentrations with morphological, histological, and molecular levels. Specifically, the malformation and dysfunction of cardiac development, including pericardial oedema, abnormal heart rate, the larger distance between the venous sinus and bulbus arteriosus (SV-BA), enlargement of the pericardial area, and aberrant motor capability, were determined after indomethacin exposure. In addition, further investigation indicated that indomethacin exposure results in myocardial apoptosis in a dose-dependent manner in zebrafish at early developmental stage. Mechanistically, our results revealed that indomethacin exposure mainly regulates key cardiac development-related genes, especially genes related to the cardiac muscle contraction-related signaling pathway, in zebrafish embryos. Thus, our findings suggested that acute indomethacin exposure might cause cardiotoxicity by disturbing the cardiac muscle contraction-related signaling pathway and inducing myocardial apoptosis in zebrafish embryos. • Indomethacin potentially results in malformation and dysfunction of cardiac development in zebrafish embryos. • Indomethacin mainly regulates genes related to the cardiac muscle contraction-related signaling pathway in zebrafish embryos. • Indomethacin exposure induces myocardial apoptosis in a dose-dependent manner in zebrafish embryos. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is the end stage of several cardiovascular diseases with high mortality worldwide; however, current chemical drugs have not beneficial effect on reducing its mortality rate. Due to its properties of multiple targets components with multiple targets, natural products derived from traditional Chinese medicine (TCM) have exerts unique effects on the amelioration of the clinical symptoms of HF, yet, TCM is not widely used in the clinic since the potential therapeutic targets have not been fully investigated. Therefore, in this review, we briefly summarized the pathophysiological mechanism of HF and reviewed the published clinical evaluations of TCM and natural products from Chinese herbs to treat HF. Then, the therapeutic potential and the underlying mechanisms by which the natural products from Chinese herb exert their protective effects were further summarized. We concluded from this review that natural products from Chinese herbs have been shown to be more effective in treating HF by targeting multiple signaling pathways, including anticardiac hypertrophy, antifibrotic, anti-inflammatory, antioxidative and antiapoptotic activities. However, the major limitations of these compounds is that there are a lack of large scale, multicenter, randomized and controlled clinical trials for their use in treatment of HF, and the toxic effects of natural products from Chinese herbs also needed further investigation. Despite these limitations, further clinical trials and experimental studies will provide a better understanding of the mechanism of natural products from Chinese herbs and promote their wide use to treat HF. [ABSTRACT FROM AUTHOR]

Cardiac apoptosis has been identified as one of the main precipitating factors of heart failure (HF) throughout the whole course of progressive disease. Limited to the lack of diagnostic markers and effective drug targets, cardiac apoptosis is still a major clinical challenge. Here, we reveal a potential novel therapeutic target for cardiac apoptosis. In the cause of the study, we found that KLHL38 was highly expressed in cardiac tissue of HF patients via GEO data‐mining, which was further verified in the heart tissue of transverse aortic constriction mice. Meanwhile, the expression of KLHL38 is negatively correlated with myocardin protein level, which is a key cardiac apoptosis regulator. The KLHL38 overexpression obviously promoted cardiomyocyte apoptosis treated with staurosporine by facilitation of myocardin's ubiquitylation and subsequent proteasomal degradation. These findings reveal a new therapeutic target, which may provide a new theoretical foundation for the treatment of myocardial apoptosis in clinical practice. [ABSTRACT FROM AUTHOR]

Preconditioning with Peoniflorin, a component of traditional Chinese prescriptions, was proposed to be a potential strategy for cardioprotection against ischemia/reperfusion (I/R) injury. However, the cardioprotective effect of Peoniflorin preconditioning has not been thoroughly confirmed, and the underlying mechanism remains unclear. Here, we examined the cardioprotective effect and its mechanism of Peoniflorin preconditioning against myocardial I/R injury. Rats were subjected to 30 min of transient ischemia followed by 2 h of reperfusion with or without Peoniflorin (100 mg/kg) prior to reperfusion. Peoniflorin preconditioning significantly limited myocardial infarct size and reperfusion arrhythmias, as well as obviously attenuated the histomorphological and micromorphological damages induced by I/R injury. The reduced myocardial injury was also associated with the anti-apoptotic effect of Peoniflorin, as evidence by decreased TUNEL-positive cells, upregulation of BCL-2 expression, and downregulation of Bax and caspase-3 expression. In an effort to evaluate the mechanism responsible for the observed cardioprotective and anti-apoptotic effect, Western blot of phosphorylated protein was performed after 20 min of reperfusion. Results showed that Peoniflorin preconditioning activated both the Akt and ERK1/2 arm of the reperfusion injury salvage kinase (RISK) pathway. To further confirm this mechanism, the PI3K signaling inhibitor LY294002 and ERK1/2 signaling inhibitor PD98059 were administered in vivo. The cardioprotective and anti-apoptotic effects of Peoniflorin preconditioning were diminished but not abolished by pretreatment with LY294002 or PD98059. Taken together, these results indicate that Peoniflorin preconditioning protects the myocardial against I/R injury and inhibits myocardial apoptosis via the activation of the RISK pathway, highlighting the potential therapeutic effects of Peoniflorin on reducing myocardial I/R injury. [ABSTRACT FROM AUTHOR]

Coronary microembolization (CME)-induced inflammatory response and cardiomyocyte apoptosis are the main contributors to CME-associated myocardial dysfunction. Bezafibrate, a peroxisome proliferator-activated receptors (PPARs) agonist, has displayed various benefits in different types of diseases. However, it is unknown whether Bezafibrate possesses a protective effect in myocardial dysfunction against CME. In this study, we aimed to investigate the pharmacological function of Bezafibrate in CME-induced insults in myocardial injury and progressive cardiac dysfunction and explore the underlying mechanism. A CME model was established in rats, and cardiac function was detected. The levels of injury biomarkers in serum including CK-MB, AST, and LDH were determined using commercial kits, and pro-inflammatory mediators including TNF-α and IL-6 were detected using ELISA kits. Our results indicate that Bezafibrate improved cardiac function after CME induction. Bezafibrate reduced the release of myocardial injury indicators such as CK-MB, AST, and LDH in CME rats. We also found that Bezafibrate ameliorated oxidative stress by increasing the levels of the antioxidant GPx and the activity of SOD and reducing the levels of TBARS and the activity of NOX. Bezafibrate inhibited the expression of pro-inflammatory cytokines such as TNF-α and IL-6. Importantly, Bezafibrate was found to mitigate CME-induced myocardial apoptosis by increasing the expression of Bcl-2 and reducing the levels of Bax and cleaved caspase-3. Mechanistically, Bezafibrate could prevent the activation of p38 MAPK/NF-κB signaling. These findings suggest that Bezafibrate may be a candidate therapeutic agent for cardioprotection against CME in clinical applications.

Acute myocardial infarction (AMI) is characterized by myocardial tissue necrosis and activation of inflammatory response. This study aims to elucidate the potential mechanism underlying the protective effects of long non-coding RNA (lncRNA) highly up-regulated in liver cancer (HULC) against myocardial ischemia/reperfusion (I/R) injury in rat models and apoptosis of cardiomyocytes. We firstly established rat models of myocardial I/R injury and rat cardiomyocyte (H9c2 cells) models of hypoxia/reoxygenation (H/R) injury. Sprague-Dawley (SD) neonatal rats were randomized into four groups: sham, I/R, I/R+ microRNA (miR) −377-5p mimic, and I/R+ miR-377-5p antagomir, respectively. Then, histopathological examination was applied. Apoptosis was evaluated by transferase-mediated dUTP nick end labeling (TUNEL) staining. Cell vitality was measured using MTT assay. The concentrations of creatine kinase MB (CK-MB), cardiac troponin I (cTnI), interleukin (IL) −6 (IL-6), and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The expression of Cleaved-Caspase-3, Caspase-3, NOD-like receptor P3 (NLRP3), Caspase-1, and IL-1β was analyzed by immunohistochemical (IHC) or Western blot analysis. We found that HULC was downregulated and miR-377-5p was upregulated in IR-injured myocardial tissue and the H/R-induced H9c2 cell. Overexpression of miR-377-5p increased myocardial dysfunction and apoptosis and activated formation and secretion of IL-6 and TNF-α. The preprocessing of miR-377-5p silencing emerged opposite results. Strikingly, dual luciferase reporter assay showed that HULC was a sponge of miR-377-5p. Subsequently, mechanism experiments revealed that NLRP3/Caspase‑1/IL‑1β was a target axis of miR-377-5p. In vitro, the protective effect of HULC overexpression on H9c2 cell viability and inflammation was offset by miR-377-5p silencing. Finally, rescue assay suggested that HULC-miR-377-5p -NLRP3/Caspase‑1/IL‑1β axis regulated the apoptosis and inflammation of H/R-induced H9c2 cells. Overall, these results indicate that the protective effect of HULC against myocardial I/R injury and H/R cardiomyocyte apoptosis partially relies on the inhibition of NLRP3/Caspase‑1/IL‑1β signaling pathway. [ABSTRACT FROM AUTHOR]

Background Pathophysiologic mechanisms underlying cardiac structural and functional changes in obesity are complex and linked to adipocytokines released from pericardial adipose tissue (PAT) and cardiomyocyte apoptosis. Although leptin is involved in various pathological conditions, its role in paracrine action of pericardial adipose tissue on myocardial apoptosis remains unknown. This study was designed to investigate the role of PAT‐derived leptin on myocardial apoptosis in high‐fat diet–induced obese rats. Methods and Results Hearts were isolated from lean or high‐fat diet–induced obese Wistar rats for myocardial remodeling studies. Obese rats had abnormal myocardial structure, diastolic dysfunction, greatly elevated cardiac apoptosis, enhanced cardiac fibrosis, and increased oxidative stress level. ELISA detected significantly higher than circulating leptin level in PAT of obese, but not lean, rats. Western blot and immunohistochemical analyses demonstrated increased leptin receptor density in obese hearts. H9c2 cardiomyoblasts, after being exposed to PAT‐conditioned medium of obese rats, exhibited pronounced reactive oxygen species–mediated apoptosis, which was partially reversed by leptin antagonist. Moreover, leptin derived from PAT of obese rats inhibited Na+/K+‐ATPase activity of H9c2 cells through stimulating reactive oxygen species, thereby activating calcium‐dependent apoptosis. Pretreatment with specific inhibitors revealed that Janus kinase 2/signal transducer and activator of transcription 3 and phosphoinositide 3‐kinase/protein kinase B signaling pathways were involved in leptin‐induced myocardial apoptosis. Conclusions PAT‐derived leptin induces myocardial apoptosis in high‐fat diet–induced obese rats via activating Janus kinase 2/signal transducer and activator of transcription 3/reactive oxygen species signaling pathway and inhibiting its downstream Na+/K+‐ATPase activity.

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress.

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress. [ABSTRACT FROM AUTHOR]

To explore the inhibitory effects of Astragalus polysaccharide on myocardial apoptosis induced by hypoxia/reoxygenation in rats based on the high mobility group box 1/toll-like receptor 4/nuclear factor kappa B signaling pathway. The hypoxia/reoxygenation injury model of H9C2 myocardial cells was established and divided into control group, hypoxia/reoxygenation group, Astragalus polysaccharide group and high mobility group box 1 inhibitor group. Cell proliferation and apoptosis were detected by cell counting kit-8 assay and Annexin V-fluorescein isothiocyanate/propidium iodide double staining. The messenger RNA expressions of high mobility group box 1, toll-like receptor 4 and nuclear factor kappa B were detected by quantitative reverse transcription polymerase chain reaction and the contents of tumor necrosis factor alpha, interleukin-1ß and interleukin-6 were determined using enzyme-linked immunosorbent assay. Compared with control group, cell proliferation was significantly weakened, apoptosis was significantly enhanced and the messenger RNA expressions of high mobility group box 1, toll-like receptor 4 and nuclear factor kappa B and the contents of tumor necrosis factor alpha, interleukin-1ß and interleukin-6 significantly increased in hypoxia/reoxygenation group (p<0.05). Compared with hypoxia/reoxygenation group, Astragalus polysaccharide group and high mobility group box 1 inhibitor group had significantly enhanced cell proliferation, weakened apoptosis and decreased messenger RNA expressions of high mobility group box 1, toll-like receptor 4 and nuclear factor kappa B and contents of tumor necrosis factor alpha, interleukin-1ß and interleukin-6 (p<0.05). Astragalus polysaccharide can repair the hypoxia/reoxygenation injury of H9C2 myocardial cells, which may suppress apoptosis through inhibiting the high mobility group box 1/toll-like receptor 4/nuclear factor kappa B signaling pathway. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) causes heart failure and increases the mortality in diabetic patients. Myocardial apoptosis and fibrosis are the main features of DCM and aging. The aim is to study the underlying mechanism of D-pinitol (DP) on myocardial apoptosis and fibrosis in an elderly diabetic mouse model. The diabetic model was established by SAMP-8 mice that were injected with streptozotocin daily for five consecutive days. The mice were administrated of DP (150 mg kg-1 day-1) by gavage for 10 weeks. The common metabolic disorder indices, cardiac dysfunction, oxidative stress, myocardial apoptosis and fibrosis, and PI3K/Akt/mTOR pathway were investigated. Our findings suggested that DP has a protective effect on DCM, which may be related to regulating oxidative stress, and PI3K/Akt/mTOR pathway involving cardiac fibrosis and apoptosis. DP may be a novel clinical application in fighting against DCM. Practical applications: D-pinitol (DP) was found in large quantities in soybean and legume foods. DP has a variety of functions, including hypoglycemic, anti-oxidation, anti-inflammatory, cardioprotective, and anti-tumor activity. We used the streptozotocin-induced SAMP8 mice as the diabetic model and treated with DP. We found that DP can improve cardiac dysfunction and inhibits the oxidative stress, myocardial apoptosis and fibrosis. DP has a significant effect on diabetic cardiomyopathy (DCM). The molecular mechanisms are related to regulating oxidative stress, and PI3K/Akt/mTOR pathway involving cardiac fibrosis and apoptosis. DP can prevent and/or delay the onset of DCM. [ABSTRACT FROM AUTHOR]

The biological effect of atrial natriuretic peptide (ANP) in traumatic hemorrhagic shock (THS) is unknown. This study was to evaluate whether ANP therapy can show organ protection in THS. Thirty male Sprague-Dawley rats were divided into three groups: ANP group, sham group, and control group. Pressure-controlled THS was induced in rats in ANP group and control group. ANP at a rate of 0.025 μg/kg/min was infused in ANP group during near-80 min of shock. After that, animals were resuscitated for 60 min and observed until 24 h. Hemodynamic parameters during shock and resuscitation were measured. Serum levels of ANP and lactate dehydrogenase, tissue oxidative stress and inflammatory factors, as well as liver and kidney function were determined. Tissue apoptosis was also assessed. There was no statistically significant difference between ANP group and control group in arterial pressure throughout the 150 min monitoring period. Blood urea nitrogen at 90 min and 24 h in ANP group was significantly lower than control group. Alanine transaminase and aspartate aminotransferase activity at 90 min in control group were significantly higher than that in sham group. However, hepatic enzyme activity at 90 min in ANP group was not significantly different compared with sham or control group. After 24 h, myocardial expression of caspase 3 protein in ANP group was significantly reduced compared with control group. Jejunal and hepatic Malondialdehyde was increased following ANP treatment. ANP therapy during early THS has no significant adverse effect on hemodynamics but can exert oxidative stress and certain protective effect on multiple organs. Our study may shed light on the novel therapy of THS with regard to organ protection. The mechanisms underlying the organ protection require further study. [ABSTRACT FROM AUTHOR]

Background. Puerarin demonstrates a protective effect in many cardiovascular diseases. However, the role of puerarin in acute myocardial infarction (AMI)-induced injury and the exact molecular mechanisms are not fully understood. Objectives. To investigate whether puerarin pretreatment improves cardiac function and to study the mechanism of action of puerarin. Materials and methods. Thirty rats were grouped into sham group, AMI group and AMI+puerarin (PUE) group at random (n = 10 per group). Except for the sham group, a model of AMI was established via left anterior descending artery ligation. The PUE group received puerarin 120 mg/(kg × day) for 7 days before the operation. Echocardiography was used for evaluation of cardiac function in rats and TUNEL staining for measuring myocardial apoptosis. The expression levels of p-PI3K, t-Akt, p-Akt, Bax, Bcl-2, and cleaved caspase-3 proteins were measured with western blot. Results. Compared to the sham group, the AMI group demonstrated poor cardiac function and decreased p-PI3K, p-Akt and Bcl-2 proteins levels, while Bax, cleaved caspase-3, and myocardial apoptosis levels increased. Compared with the AMI group, the PUE group showed significant improvement in cardiac function and increased protein expression of p-PI3K, p-Akt and Bcl-2, while Bax and cleaved caspase-3 levels decreased and myocardial apoptosis was attenuated. Conclusions. Puerarin pretreatment in AMI can effectively improve cardiac function by inhibiting myocardial apoptosis. The molecular mechanism of this protective effect may be mediated by activating the PI3K/Akt pathway in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Objectives To assess the effect of sildenafil on monocrotaline-induced right ventricular (RV) remodeling and investigate the possible mechanism. Methods Rats were subcutaneously injected with monocrotaline to establish an RV remodeling model and then administered sildenafil (25 mg/kg) from days 1 to 28. After 28 days of administration, the RV systolic pressure and the RV hypertrophy index (RVHI) were measured. The morphology of the right ventricle was observed by H&E staining. The ultrastructure of the right ventricle was observed using a transmission electron microscope. The myocardial apoptosis of the right ventricle was evaluated by TUNEL staining. The protein expression of apoptosis-related proteins and PPARs were examined by western blotting. Key findings The results indicated that sildenafil decreased the RV systolic pressure and RVHI, and improved the microstructure and ultrastructure of the right ventricle in monocrotaline-induced rats. In addition, sildenafil suppressed myocardial apoptosis and promoted the protein expression of PPARs of the right ventricle in monocrotaline-induced rats. Conclusion Sildenafil inhibits RV remodeling in monocrotaline-induced rats, which might be partially mediated by reducing myocardial apoptosis and activating PPARs. [ABSTRACT FROM AUTHOR]

Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

Abstract Background Myocardial apoptosis is important in the pathogenesis and progression of myocardial infarction-induced heart failure (MI-HF). Renal sympathetic denervation (RDN) has become a promising therapeutic strategy for the treatment of HF. Previous studies have shown that RDN could improve heart function Yao et al. (Exp Ther Med 14:4104-4110, 2017). However, whether and how RDN regulates myocardial apoptosis in MI-HF is unclear. This study sought to evaluate the effects of RDN on cardiac function and apoptosis-related gene expression in MI-HF dogs. Methods Eighteen healthy mongrel dogs were randomly divided into control group(n = 6), model group(n = 6) and treatment group(n = 6). MI-HF was established in model group and treatment group by anhydrous alcohol embolization, after heart failure dogs in the treatment group and model group proceeded bilateral renal artery ablation and bilateral renal arteriography, respectively. The cardiac function parameters were evaluated by echocardiographic; the serum NT-BNP level was detected by ELISA; the degree of myocardial fibrosis was observed through masson staining; the expression of MMP-2, MMP-9 in the cardiac were got by immunohistochemistry. TUNEL method was used to observe cardiomyocyte apoptotsis and calculate the apoptosis index (AI). Relative expression of Bcl-2 and Bax, Caspase3 and GRP78 were detected using RT-PCR and Western Blot. Renal artery H&E staining and serum creatinine were conducted to access the efficacy and safety of RDN. Results Four weeks after RDN, the LVEDD, LVESD and LVEDP decreased, and the LVEF and LVSP increased in the treatment group compared with those in the control group (all P

Objective: Over the years, the roles of microRNAs (miRNAs) and histone deacetylase 3 (HDAC3) in human diseases have been investigated. This study focused on the effect of miR‐19a‐3p and HDAC3 in myocardial ischemia–reperfusion (I/R) injury (MIRI) by targeting cyclin‐dependent kinase 2 (CDK2). Methods: The I/R rat models were established by coronary artery ligation, which were then treated with RGFP966 (an inhibitor of HDAC3), miR‐19a‐3p agomir or antagomir, or silenced CDK2 to explore their roles in the cardiac function, pathological changes of myocardial tissues, myocardial infarction area, inflammatory factors and oxidative stress factors in rats with MIRI. The expression of miR‐19a‐3p, HDAC3, and CDK2 was determined by RT‐qPCR and western blot assay, and the interaction among which was also verified by online prediction, luciferase activity assay and ChIP assay. Results: The results indicated that HDAC3 and CDK2 were upregulated while miR‐19a‐3p was downregulated in myocardial tissues of I/R rats. The inhibited HDAC3/CDK2 or elevated miR‐19a‐3p could promote cardiac function, attenuate pathological changes, inflammatory reaction, oxidative stress, myocardial infarction area and apoptosis of myocardial tissues. HDAC3 mediates miR‐19a‐3p and CDK2 is targeted by miR‐19a‐3p. Conclusion: Inhibited HDAC3 ameliorates MIRI in a rat model by elevating miR‐19a‐3p and reducing CDK2, which may contribute to the treatment of MIRI. [ABSTRACT FROM AUTHOR]

Myocardial injury caused by the myocardial ischaemia (MI) is still a troublesome condition in the clinic, including apoptosis, oxidative stress and inflammation. Diosmetin inhibits the cellular apoptosis and inflammatory response and enhances antioxidant activity. So, this study was designed to investigate the cardioprotective effects of diosmetin on MI model neonatal rats. Forty Sprague Dawley (SD) rats 7 days old were randomly divided into five groups. Four groups of rats received diosmetin (50, 100, and 200 mg/kg) or vehicle (MI group) after ischaemia. Another group received vehicle without ischaemia to serve as a control group. Rats were pretreated with diosmetin intraperitoneally for 7 days and intoxicated with isoproterenol (ISO, 85 mg/kg, sc) on the last 2 days. The expression of apoptotic molecules, myocardial systolic function index, antioxidant enzymes and myocardial enzyme was analyzed. Compared with the control group, the proliferation marker proteins of Ki67 were increased significantly (P <.05), the MI group significantly increased the cardiac apoptosis, oxidative stress and myocardial enzymes, and weakened myocardial contractility. The levels of p‐P65/P65 were increased significantly (P <.05) with decreased p‐AKT/AKT and p‐Nrf2/Nrf2 (P <.05). Nevertheless, pretreatment with diosmetin reversed these changes, especially high‐dose group. In summary, diosmetin has significant potential as a therapeutic intervention to ameliorate myocardial injury after MI and provides the rationale for further clinical studies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of Composition of Ophiopogon polysaccharide, Notoginseng total saponins and Rhizoma Coptidis alkaloids (CONR) on myocardial apoptosis of diabetic atherosclerosis (DA) rabbits Methods: Sixty male New Zealand white rabbits were randomly divided into 6 groups [control group, model group, CONR high-dose group (450 mg/kg), CONR medium-dose group (150 mg/kg), CONR low-dose group (50 mg/kg), and simvastatin group] by using a completely random method, 10 in each group. DA model was established by intravenously injected alloxan combined with high-fat diet and abdominal aortic balloon injury. After mediation for 10 weeks, fasting blood glucose (FBG), glycosylated hemoglobin (GHB), glycosylated serum protein (GSP), fructoseamine (FRA), aldose reductase (AR), advanced glycation end products (AGEs) in serum were measured by enzyme linked immunosorbent assay (ELISA) method; the expression of receptor of AGEs (RAGE) in myocardial tissue were observed by immunohistochemical method; and p-Jun N-terminal kinase (p-JNK), caspase-3, B-cell lymphoma-2 (bcl-2) protein expression in myocardial tissue were measured by Western blotting. The myocardial apoptosis was detected by TdT-mediated dUTPnick-end labeling (TUNEL) method, and apoptosis index (AI) was calculated. Results: Compared with the control group, serum FBG, GHB, GSP, FRA, AR, AGEs and the expression of myocardium RAGE, p-JNK, caspase-3 proteins, as well as apoptosis index (AI) were significantly increased and bcl-2 protein was significantly decreased in the model group (P<0.01). Compared with the model group, the levels of serum FBG, GHB, GSP, FRA and AR showed a significant decline in CONR high- and medium-dose groups (P<0.01). FBG and GHB showed a significant decline in CONR low-dose group (P<0.01). Compared with the model group, the expression of serum AGEs and myocardium RAGE, p-JNK and caspase-3 protein as well as AI were significantly decreased and bcl-2 protein was significantly up-regulated in all treatment groups (P<0.01); high-dose CONR had the most significant effect on abovementioned indices compared with other treatment groups (P<0.01). Middle-dose CONR had better effect on serum AGEs compared with the low-dose group (P<0.01); middle-dose CONR and simvastatin groups had better effect on the expression of caspase-3, bcl-2 protein, myocardium apoptosis compared with the CONR low-dose group (P<0.01). Conclusion: CONR may effectively inhibit myocardial apoptosis on DA rabbits by intervening AGEs-RAGE and JNK, caspase-3, and bcl-2 protein expressions. [ABSTRACT FROM AUTHOR]

To investigate effects of different doses of atorvastatin on serum lipids, cardiomyocyte apoptosis and related genes in rats with myocardial infarction. 60 SD rats were randomized into control group (n = 12) and modeling group (n = 48). The models were established by ligation of left anterior descending (LAD) in rats. 5wk later, the rates after successful modeling were divided into modeling group (n = 12) and treatment group (n = 36), and treatment group was equally divided into low dose group (20 mg/kg atorvastatin daily), medium does group (40 mg/kg atorvastatin daily) and high does group (80 mg/kg atorvastatin daily). After administration, the ratio of heart weight (HW) to body weight (BW) was calculated (HW/BW). Contents of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and moderate – high density lipoprotein cholesterol (HDL-C) in serum of rats were measured. Apoptosis index of rat cardiomyocytes was detected with TUNEL method. Expression levels of Caspase-3, Bax, and Bcl-2 proteins in each group were detected by Western blot. Compared with control group, heart surface of modeling group was rough, and weight of model group was significantly higher than that of control group, low, medium and high dose groups after 9 weeks of modeling (P < 0.05). TC, TG, and LDL-C in modeling group were significantly higher than those in control group (P < 0.05), HDL-C was significantly lower than those in control group (P < 0.05). Changes in blood lipid-related indicators could be improved after administration, and the higher the dose, the better the improvement effect. Apoptosis index of cardiomyocytes in modeling group, the low, medium and high dose group was significantly higher than that in control group (P < 0.05), but apoptosis of cardiomyocytes was significantly reduced in atorvastatin group at different doses. The higher the dose, the more obvious the reduction effect. The expressions of Caspase-3, Bax, and Bcl-2 proteins in modeling group, low, medium and high dose groups were significantly higher than those in control group (P < 0.05), but administration group significantly reduced apoptosis of myocardial cells, and the higher the dose, the more significant the reduction effect. Atorvastatin can reduce TC, TG and LDL-C levels and increase HDL-C level in blood lipids, inhibit expressions of Caspase-3 and Bax and raise expression of Bcl-2 protein so as to inhibit cardiac hypertrophy, reduce cardiomyocyte apoptosis, restore myocardial function and improve myocardial infarction symptoms. [ABSTRACT FROM AUTHOR]

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. Methods: C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. Results: The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Conclusion: Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury.

Abstract Background The role of 1,25-dihydroxyvitamin D3 (vitamin D) in the apoptosis of diabetic cardiomyopathy (DCM) is unclear. This study is to investigate the effects of vitamin D on the pathological changes in rats with DCM. Methods Rats were randomly divided into the control, model, and treatment groups. DCM model was established by the high-fat and -sugar diet. Plasma glucose, body weight, heart weight, heart weight index, and serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were determined. Heart tissue morphology was detected with histochemical staining. Expression levels of Fas and FasL were detected with RT-PCR and immunohistochemistry. Results Compared with the control group, the body weights and heart weights were significantly declined, while the plasma glucose levels and heart weight indexes were significantly elevated, in the model group (P

OBJECTIVE: To investigate the effects of ranolazine on the cardiac function and myocardial apoptosis in rats with heart failure and its possible mechanisms. MATERIALS AND METHODS: Thirty Wistar rats were randomly divided into sham operation (negative control; NC), chronic heart failure (CHF), and ranolazine groups. Suprarenal abdominal aortic coarctation was used to induce CHF in rats. Five weeks later, rats in the ranolazine group received ranolazine (50 mg/kg) daily, whereas those in the CHF group received normal saline. After 4 weeks, changes in hemodynamic parameters, cardiac structure and pathology, myocardial apoptosis, and protein expression were assessed. RESULTS: The left ventricular end-diastolic pressure (LVEDP) significantly increased in the CHF group; whereas the maximal rate of left ventricular pressure rise and fall (±dp/dtmax) decreased, compared to those in the NC group. Ranolazine significantly reduced LVEDP and increased ±dp/dtmax (p<0.01), compared to those in the CHF group. Severe impairment of cardiomyocytes was observed in the CHF group with evident inflammation; however, ranolazine reversed these deficits. Rats in the CHF group exhibited an increase in TUNEL-positive cells, which was inhibited by ranolazine, where the apoptotic index significantly decreased in ranolazine-treated rats (p<0.01). Also, ranolazine downregulated caspase-9 expression and upregulated pAKT and Bcl-2 expression in rat cardiomyocytes. Moreover, ranolazine significantly inhibited myocardial apoptosis and caspase-9 expression, promoted AKT phosphorylation, and upregulated pAKT and Bcl-2 expression in vitro, compared to those in the control group (p<0.001). LY294002 inhibited ranolazine-induced suppression of myocardial apoptosis (p<0.001). CONCLUSIONS: Ranolazine improved cardiac function and inhibited myocardial apoptosis in rats with CHF, which could be attributed to the regulation of AKT phosphorylation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to investigate whether microRNA-221 could promote cardiomyocyte apoptosis by down-regulating the expression of PTEN (gene of phosphate and tension homology deleted on chromosome ten), thereby participating in the development of myocardial ischemia-reperfusion. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRTPCR) was used to analyze the expression levels of microRNA-221 and PTEN in human cardiomyocytes (HCM) cells treated with hypoxia/reoxygenation (H/R). The expressions of myocardial injury markers, including lactic dehydrogenase enzyme (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were determined by qRT-PCR as well. The binding relationship between microRNA- 221 and PTEN was verified by the Dual-Luciferase reporter gene assay. Subsequently, microRNA-221 inhibitor and si-PTEN were transfected into cells. The proliferation and apoptosis of cells were analyzed using Cell Counting Kit-8 (CCK-8) and flow cytometry, respectively. In addition, the expression levels of apoptosis-related proteins were determined by Western blot. RESULTS: The qRT-PCR results confirmed that the expression level of microRNA-221 in H/R treated cells was significantly up-regulated when compared with the normoxic treated group, whereas PTEN expression was markedly down-regulated. After silencing microRNA-221, the expression levels of myocardial injury markers, including LDH, MDA, GSH-PX in H/R cells were significantly decreased. However, SOD levels were remarkably increased. At the same time, down-regulation of microRNA-221 markedly increased cell proliferation, whereas decreased apoptosis. However, microRNA-221 enhanced the expression of apoptosis-related genes, including Bax and cytochrome C. Meanwhile, the expression level of anti-apoptotic gene Bcl-2 was significantly inhibited. The Dual-Luciferase reporter gene assay showed that microRNA-221 could target bind to PTEN and inhibit its expression. Similarly, down-regulation of PTEN markedly decreased cell proliferation and increased cell apoptosis. Furthermore, PTEN down-regulation remarkably promoted protein expression of pro-apoptosis-related genes, whereas inhibited the protein expression of anti-apoptotic genes. CONCLUSIONS: MicroRNA-221 promoted myocardial apoptosis induced by myocardial ischemia- reperfusion by down-regulating PTEN. Therefore, microRNA-221 might be a potential therapeutic target for myocardial ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the effect of interleukin-6 (IL-6) gene knockout on apoptosis of myocardial cells in mice with Coxsackievirus B3 (CVB3)-induced dilated cardiomyopathy (DCM) and its potential mechanism, so as to provide certain references for the clinical prevention and treatment of DCM. MATERIALS AND METHODS: A total of 40 male C57 mice were randomly divided into Sham group (n=20) and DCM group (n=20) using a random number table. Another 20 mice with IL-6 gene knockout were enrolled into DCM+IL-6 KO group (n=20). The DCM model was established via CVB3 repeated incremental infection. After 9 months, the heart weight/body weight (HW/BW) ratio of mice in each group was detected. The ejection fraction [EF (%)] and fraction shortening [FS (%)] of mice in each group were detected via two-dimensional ultrasonography. The cross-sectional area and pathological changes in myocardial cells in the heart in each group were determined using hematoxylin-eosin (HE) staining. The collagen content in myocardial tissues in each group was detected via Masson staining and picrosirius red (PSR) staining, and the expressions of Collagen I and Collagen III in myocardial tissues in each group were detected via immunohistochemistry. In addition, the myocardial apoptosis in myocardial tissues in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Finally, the protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and total STAT3 (t-STAT3) were detected via Western blotting. RESULTS: The expression of IL-6 messenger ribonucleic acids (mRNAs) in myocardial tissues in DCM group was significantly increased compared with that in Sham group (p<0.05). After IL-6 knockout, the HW/BW ratio of DCM mice significantly declined (p<0.05), and the cross-sectional area of myocardial cells was significantly reduced (p<0.05). According to the results of echocardiography, the cardiac function of mice in DCM+IL-6 KO group was significantly superior to that in DCM group, manifested as the significant increase in FS (%) and EF (%) (p<0.05). The results of Masson staining, PSR staining, and immunohistochemical staining showed that IL-6 knockout could reduce the collagen content and Collagen I and Collagen III expressions in myocardial tissues of DCM mice (p<0.05). Furthermore, it was found via TUNEL staining that the number of apoptotic myocardial cells in DCM+IL-6 KO group was markedly smaller than that in DCM group (p<0.05). At the same time, the Bax/Bcl-2 ratio in myocardial tissues in DCM+IL-6 KO group was lower (p<0.05). Finally, the results of Western blotting revealed that DCM+ IL-6 KO group had a lower phosphorylation level of STAT3 than DCM group (p<0.05). CONCLUSIONS: Inhibiting IL-6 gene may improve the DCM-induced myocardial remodeling through reducing myocardial apoptosis. [ABSTRACT FROM AUTHOR]

Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R). Toll-like receptor 4 (TLR4) is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105) is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI). Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham). After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.

OBJECTIVE: This study aims at investigating whether GAS5 (grow arrest-specific 5) could promote cardiomyocyte apoptosis by upregulating LAS1 expression, thereby participating in the development of myocardial ischemia-reperfusion injury. MATERIALS AND METHODS: The expression level of GAS5 in H9c2 cells after hypoxia/reoxygenation (H/R) treatment was detected by quantitative Real time-polymerase chain reaction (qRT-PCR). Myocardial injury markers in H9c2 cells were evaluated using relative commercial kits, including activities of LDH (lactate dehydrogenase), MDA (malondialdehyde), SOD (superoxide dismutase) and GSH-PX (glutathione peroxidase). Cell proliferation and apoptosis were detected by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The protein expressions of apoptosis-related genes and p38/MAPK pathway-related genes were detected by Western blot. The regulatory effects of GAS5 on the p38/MAPK pathway were assessed after treatment with p38/MAPK pathway inhibitor in H9c2 cells. RESULTS: QRT-PCR results showed that the expression levels of GAS5 and LAS1 in H/R-treated H9c2 cells were remarkably upregulated compared to those of controls. GAS5 overexpression increased activities of LDH, MDA, SOD and GSH-PX in H/R-treated H9c2 cells. Meanwhile, GAS5 overexpression reduced cell proliferation and apoptosis of H/R-treated cells. Western blot results suggested that the pro-apoptosis genes Bax and cytochrome C were upregulated, whereas the anti-apoptosis gene Bcl-2 was downregulated after GAS5 overexpression. The overexpression of LAS1 in H9c2 cells obtained the same results as GAS5 overexpression. Furthermore, the expressions of p-p38 and p-ERK were upregulated by GAS5 overexpression. SB203580, the p38/MAPK pathway inhibitor, could reverse the inhibited proliferation and increase apoptosis induced by overexpression of GAS5. CONCLUSIONS: GAS5 promotes myocardial apoptosis in myocardial ischemia-reperfusion injury by upregulating LAS1 expression via p38/MAPK pathway. GAS5 may be a potential therapeutic target for myocardial ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the cardioprotective mechanisms of exercise preconditioning (EP). MATERIALS AND METHODS: Eighty male Sprague-Dawley (SD) rats were randomized into the Group control, Group EE, Group EP+EE, Group EP+EE+AG, and Group EE+AG. By using 3 days of intermittent treadmill exercise, this study established the EP animal model. Rats were subjected to run to exhaustion on the treadmill at 30 m/min with 0% grade as an exhaustive exercise (EE) protocol. The myocardial injury induced by exhaustive exercise was produced 24 h after EP. JAK2 inhibitor (AG490, 3 mg/kg) was injected before EP. Serum cardiac troponin I (cTnI) levels and hematoxylin basic fuchsine picric acid (HBFP) staining were used to observe the degree of myocardial ischemia. TUNEL, Bcl2, and cleaved caspase-3 levels were used to evaluate the change of myocardial apoptosis. Moreover, the phosphorylations of JAK2 and STAT3 were analyzed as possible mechanisms that might explain the EP-induced cardioprotection. RESULTS: EP significantly attenuated the exhaustive exercise-induced myocardial ischemia injury, associated with lower serum cTnI levels, decreased myocardial infarct area, reduced myocardial apoptosis, increased Bcl2 level, decreased cleaved caspase-3 level, and the increased phosphorylations of JAK2 and STAT3. Treatment with AG490 abolished the cardioprotective effects and the enhanced phosphorylations of JAK2 and STAT3 induced by EP. CONCLUSIONS: EP plays its cardioprotective role via activating the JAK2/STAT3 signaling pathway, reducing the apoptosis of myocardial cells and alleviating myocardial ischemia injury. [ABSTRACT FROM AUTHOR]

Background: Myocardial apoptosis is important in the pathogenesis and progression of myocardial infarction-induced heart failure (MI-HF). Renal sympathetic denervation (RDN) has become a promising therapeutic strategy for the treatment of HF. Previous studies have shown that RDN could improve heart function Yao et al. (Exp Ther Med 14:4104-4110, 2017). However, whether and how RDN regulates myocardial apoptosis in MI-HF is unclear. This study sought to evaluate the effects of RDN on cardiac function and apoptosis-related gene expression in MI-HF dogs.Methods: Eighteen healthy mongrel dogs were randomly divided into control group(n = 6), model group(n = 6) and treatment group(n = 6). MI-HF was established in model group and treatment group by anhydrous alcohol embolization, after heart failure dogs in the treatment group and model group proceeded bilateral renal artery ablation and bilateral renal arteriography, respectively. The cardiac function parameters were evaluated by echocardiographic; the serum NT-BNP level was detected by ELISA; the degree of myocardial fibrosis was observed through masson staining; the expression of MMP-2, MMP-9 in the cardiac were got by immunohistochemistry. TUNEL method was used to observe cardiomyocyte apoptotsis and calculate the apoptosis index (AI). Relative expression of Bcl-2 and Bax, Caspase3 and GRP78 were detected using RT-PCR and Western Blot. Renal artery H&E staining and serum creatinine were conducted to access the efficacy and safety of RDN.Results: Four weeks after RDN, the LVEDD, LVESD and LVEDP decreased, and the LVEF and LVSP increased in the treatment group compared with those in the control group (all P < 0.05). Moreover, NT-BNP, an indicator of cardiac function was decreased. Additionally, MMP-2 and MMP-9 levels in the myocardium decreased significantly in the treatment group. Furthermore, the levels of Bax, and caspase 3 decreased, while the level of Bcl-2 increased. Thus, myocardial apoptosis was attenuated in RDN treated dogs. We also found that the level of GRP78 which is activated in response to endoplasmic reticulum (ER) stress, was decreased. However, serum creatinine levels were not significantly different between the RND-treated dogs and the control dogs.Conclusion: Cardiac function was improved by RDN treatment through regulating apoptosis and ER stress in cardiomyocytes in dogs after MI. [ABSTRACT FROM AUTHOR]

Epidemiological studies have confirmed that ambient fine particulate matter (PM2.5) exposure is associated with cardiovascular disease (CVD). However, the underlying mechanisms in PM2.5 exposure-induced heart injury are largely unknown. It has been acknowledged that NADPH oxidase (Nox) 4 plays a critical role in CVD development. To investigate the acute effects of PM2.5 on the mouse heart and the role of Nox4 in PM2.5 exposure-induced cardiac injury, C57BL/6J mice were instilled with saline or 1.5, 3.0, 6.0 mg/kg BW PM2.5 suspension for two weeks (five days per week). The levels of malondialdehyde (MDA), super oxide dismutase (SOD), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in heart supernatants were determined using related kits. The expression of Nox4, p67phox, p47phox and p22phox in heart tissue was evaluated by immunofluorescence staining or Western blotting, respectively. Protein levels of p53, Bax, Bcl-2 and Caspase-3 in the heart were examined using immunohistochemical staining and Western blotting. TUNEL assay was used to measure myocardial apoptosis. PM2.5 exposure leads to obvious cardiac injury. PM2.5 exposure increases MDA level and iNOS activity, and decreases activity of SOD in heart supernatants of mice. High levels of TNF-α and IL-1β in heart supernatants of mice with PM2.5 instillation were determined. Nox4 and Nox-associated subunits such as p67phox, p47phox and p22phox expression levels were increased in heart tissue of mice after PM2.5 exposure. Additionally, PM2.5 exposure causes myocardial apoptosis in the mouse heart. This study suggested that Nox4 is involved in PM2.5 exposure-induced cardiac injury in mice. [ABSTRACT FROM AUTHOR]

Backgrounds: Fisetin (tetrahydroxyflavone), a natural plant component, is known to have different properties including, direct radical scavenger, anti-inflammation, and cell survival.Methods: We investigated whether fisetin can protect cardiomyocytes against H2O2-induced apoptosis that is relevant to cardiovascular disease risks using cell viability test, ROS measurement, and Western blotting.Results: Fisetin decreased apoptotic cell death and intracellular reactive oxygen species (ROS), while enhancing the expression of Cu/Zn-superoxide dismutase (SOD) as well as phosphorylation of Akt and extracellular regulated kinase (ERK) 1/2. In particular, fisetin significantly decreased apoptosis through inhibition of cleaved caspase-3 and Bax expression and by enhancing the expression of anti-apoptotic enzyme as well as Bcl-2 in H2O2-stimulated H9c2 cells. However, the expression of heme oxygenase, catalase, and Mn-SOD was not altered by fisetin in these conditions.Conclusion: Taken together, these data suggest that the potential cardioprotective effect of fisetin may involve Cu/Zn-SOD-mediated activation of Bcl-2 through the Akt and ERK1/2 pathways. [ABSTRACT FROM AUTHOR]