The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation.

Rationale: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation. Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment. Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

Qualitative and quantitative analysis of the chemical profile for Gualou-Xiebai-Banxia decoction, a classical traditional Chinese medicine formula for the treatment of coronary heart disease, by UPLC-Q/TOF-MS combined with chemometric analysis.

Gualou-Xiebai-Banxia decoction (GXB) is one of the famous classical traditional Chinese Medicine (TCM) formula for the treatment of chest stuffiness and pains syndrome in Chinese medicine, i.e., coronary heart disease (CHD) in modern medicine. Being compared with Gualou-Xiebai Baijiu-decoction which only consists of Trichosanthis Pericarpium (TP), Allii Macrostemonis Bulbus (AMB) and wine, GXB is composed of another one additional herbal medicine, Pinellinae Rhizoma Praeparatum (PRP), and is more suitable to treat severe atherosclerosis and dyslipidemia. However, the comprehensive chemical composition of GXB is still unclear, which has seriously hindered the discovery of its effective components for improving the clinical symptoms of CHD. The present study aimed to investigate the overall chemical profile of GXB qualitatively and quantitatively by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS), and further explore the chemical contribution of PRP to this formula combined with chemometric approach. First, a total of 151 components, including steroidal saponins, flavonoids, triterpenoids, nitrogenous and other types components, were detected and characterized by UPLC-Q/TOF-MS in GXB. Then, flavonoids and nitrogenous could be qualitatively observed enrichment in GXB compared to those in GXB-dePRP (GXB deducted PRP in the formula). Furthermore, 19 characteristic components were selected for quantitative comparison between GXB and GXB-dePRP by UPLC-MS/MS combined with chemometric method. These findings indicated that steroidal saponins were the most abundant components in GXB, while the introduction of PRP could not only enrich the structural types of chemical compounds in this formula, but also increase the abundance of active components from other composed herbal medicines, TP and AMB. Taken together, this study developed and validated sensitive and practical methods for qualitative and quantitative analysis of GXB, and clarified the chemical contribution of PRP to this formula. These results laid a solid chemical foundation for further in vivo disposal investigation to screen out the potential effective components as well as therapeutic mechanism research of GXB.

Isoproterenol Increases Left Atrial Fibrosis and Susceptibility to Atrial Fibrillation by Inducing Atrial Ischemic Infarction in Rats.

Left atrial (LA) fibrosis is a major arrhythmogenic substrate for atrial fibrillation (AF). The purpose of this study was to assess whether isoproterenol (ISO) induces LA fibrosis and increases susceptibility to AF, exploring the underlying mechanisms. Male Sprague-Dawley rats were subcutaneously injected ISO once per day for 2 days. Five weeks after injection, the ISO group had higher susceptibility AF and prolonged AF duration compared with the control group. ISO decreased LA conduction velocity (CV) and increased LA conduction heterogeneity. ISO increased fibrosise areas and the protein levels of collagen types I and III in the left atrium. Antifibrosis drug pirfenidone decreased AF occurrence and reduced LA fibrosis in ISO treated rats. ISO injection induced atrial ischemia infarction by increasing heart rate and decreasing diastolic and systolic blood pressures. These findings demonstrated that ISO increases susceptibility to AF by increasing LA fibrosis and LA conduction abnormalities 5 weeks after injection. ISO injection induces atrial ischemic injury is the main cause of fibrosis. Rats with ISO-induced LA fibrosis may be used in further AF research.

Shensong Yangxin capsule reduces atrial fibrillation susceptibility by inhibiting atrial fibrosis in rats with post-myocardial infarction heart failure.

PURPOSE: Shensong Yangxin (SSYX) capsule is a traditional Chinese medicine that has been used widely to treat cardiac arrhythmia. This study aimed to assess whether SSYX prevents atrial fibrillation (AF) after chronic myocardial infarction (MI)-induced heart failure and to determine the underlying mechanisms. MATERIALS AND METHODS: The study included 45 male Sprague Dawley rats. The rats underwent MI induction or sham surgery. One week after MI induction surgery, we performed serial echocardiography and administered SSYX capsule to some rats that experienced MI. After 4 weeks of treatment, AF inducibility was assessed with transesophageal programmed electrical stimulation technology. Additionally, multielectrode array assessment, histological analysis, and Western blot analysis were performed. RESULTS: AF inducibility was significantly lower in SSYX rats than in MI rats (33.3% vs 73.3%, P<0.05). Additionally, conduction velocities in the left atrium were greater in SSYX rats than in MI rats. Moreover, SSYX decreased left atrial fibrosis, downregulated TGF-ß1, MMP-9, TIMP-I, and type I and III collagen expressions, and inhibited the differentiation of cardiac fibroblasts to myofibroblasts. CONCLUSION: SSYX reduces AF inducibility after MI by improving left atrial conduction function via the inhibition of left atrial fibrosis. It prevents the development of an MI-induced vulnerable substrate for AF.

[Effectiveness and safety of acupuncture for supraventricular tachycardia: a systematic review and meta-analysis].

The effectiveness and safety of acupuncture for the treatment of supraventricular tachycardia were systematically reviewed. The randomized controlled trials (RCTs) regarding acupuncture for supraventricular tachycardia were searched in domestic and overseas databases, and the evaluation tool of bias risk in Cochrane Handbook 5.1.0 software was used to perform the evaluation of bias risk in literature, and RevMan 5.2 software was applied for statistics and Meta-analysis. Five RCTs involving 323 patients were included. The results showed that compared with the blank control group, the acupuncture reduced the heart rate by 18.8 times/min [95% CI (12.68, 24.92)]; the clinical effective rate in the acupuncture group was superior to that in the diltiazem group [OR= 3.11, 95% CI (1.50, 6.46)]; the difference of immediate effect between propafenone and acupuncture was not significant. No reports regarding adverse events was described in 5 RCTs. As was shown in the present evidence, acupuncture is safe and effective for the treatment of supraventricular tachycardia, but the level of evidence was low and the intensity of conclusion needed to be improved.