Shuai Mao

Phytoestrogen, tanshinone IIA diminishes collagen deposition and stimulates new elastogenesis in cultures of human cardiac fibroblasts

It has been previously reported that oral or intra-peritoneal administration of tanshinone IIA can alleviate the ventricular hypertrophy and fibrosis that develops in rats after experimental cardiac infarction. Our present studies, performed on cultures of human cardiac fibroblasts, investigated the mechanism by which tanshinone IIA produces these beneficial effects. We found that treatment of cardiac fibroblasts with 0.1-10µM tanshinone IIA significantly inhibited their deposition of collagen I, while enhancing production of new elastic fibers. Moreover, both anti-collagenogenic and pro-elastogenic effects of tanshinone IIA occurred only after selective activation of the G protein-coupled estrogen receptor (GPER). This subsequently leads to initiation of the PKA/CREB phosphorylation pathway that inversely modulated transcription of collagen I and elastin genes. Interestingly, treatment of human cardiac fibroblasts with tanshinone IIA additionally up-regulated the production of the 67-kDa elastin binding protein, which facilitates tropoelastin secretion, and increased synthesis of lysyl oxidase, catalyzing cross-linkings of tropoelastin. Moreover, tanshinone IIA also caused up-regulation in the synthesis of collagenolytic MMP-1, but down-regulated levels of elastolytic MMP-2 and MMP-9. In summary, our data validate a novel mechanism in which tanshinone IIA, interacting with a non-classic estrogen receptor, maintains the proper balance between the net deposition of collagen and elastin, allowing for optimal durability and resiliency of the newly deposited matrix.

Tanshinone IIA inhibits angiotensin II induced extracellular matrix remodeling in human cardiac fibroblasts — Implications for treatment of pathologic cardiac remodeling

Article history: Received 26 July 2015 Accepted 21 August 2015 Available online 29 August 2015 Smad proteins [7]. Moreover, other evidence has suggested that Ang II has also been suggested to signal independently of Smads to promote fibrosis. Ang II activates downstream mitogen-activated protein kinase (MAPK) signaling pathways, including extracellular-regulated kinase (ERK) and p38. However, the activated pathways appear to context and cell-specific [8]. Although Ang II is a well-recognized positive regulator of fibroblasts

Sodium tanshinone IIA sulfonate for reduction of periprocedural myocardial injury during percutaneous coronary intervention (STAMP trial): Rationale and design

a Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China b Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China c Chinese Medicine Research Institute, Tianjin University of Chinese Medicine, Tianjin 300193, China d Physiology & Experimental Medicine, Hospital for Sick Children, Toronto M5G 0A4, Canada

The Antidiabetic Hormone Glucagon-Like Peptide-1 Induces Formation of New Elastic Fibers in Human Cardiac Fibroblasts After Cross-Activation of IGF-IR

Glucagon-like peptide 1 (GLP-1) is a metabolic hormone involved in the stimulation of insulin biosynthesis and secretion. It has been recently reported that GLP-1 also exerts cardioprotective effects and facilitates functional recovery after myocardial infarction through GLP-1 receptor-mediated signaling in cardiomyocytes. GLP-1 treatment has been also demonstrated to produce sustained improvement in cardiac function in long-term studies, suggesting the involvement of mechanisms beyond the acute metabolic and cytoprotective effects. For example, the possible interaction of GLP-1 with the cardiac fibroblasts, which are responsible for the postinfarct remodeling and extracellular matrix production, has not been previously explored. Here, we report that cultures of human cardiac fibroblasts treated with GLP-1 peptides display a selective up-regulation in elastin gene expression and a consequent increase in elastic fibers production, in the absence of the classic GLP-1 receptor. Importantly, we provide experimental evidence that this GLP-1-induced elastogenesis is triggered through the cross-activation of the IGF-I receptor. Because GLP-1 does not stimulate deposition of collagen I, nor promote the proliferation or apoptosis of cultured cardiac fibroblasts, we speculate that its elastogenic effect may also contribute to the beneficial remodeling of the human heart after myocardial infarction.

Hyperuricemia and contrast-induced acute kidney injury: A systematic review and meta-analysis

BACKGROUND Hyperuricemia may be associated with an increased risk of contrast-induced acute kidney injury (CI-AKI). In recent years, studies about the relationship between them gradually appeared. We performed a systematic review and meta-analysis to investigate whether hyperuricemia is an independent risk factor for CI-AKI. METHODS Relevant studies were searched in PubMed, Embase, Cochrane Library, and CBM (Chinese Biomedical Literature database) databases until April 18, 2016, without language restriction. Observational studies evaluating serum uric acid (SUA) levels and CI-AKI risks were included. The pooled odds ratio was calculated to assess the association between hyperuricemia and risk of CI-AKI using a random-effects model. RESULTS Eighteen relevant studies involving a total of 13,084 patients met our inclusion criteria. Presence of hyperuricemia was associated with an increased risk of CI-AKI development regardless of whether the effect size was adjusted or not (unadjusted OR: 2.08, 95% CI: 1.63-2.64; adjusted OR: 1.68, 95% CI: 1.38-2.04). In-hospital mortality and cases of renal replacement therapy were significantly different between subjects with hyperuricemia and normouricemia undergoing coronary angiography (CAG) and/or percutaneous coronary intervention (PCI). CONCLUSION Hyperuricemia is independently associated with the occurrence of CI-AKI and it significantly increases the in-hospital mortality and the risk of renal replacement therapy among the patients after CAG and/or PCI. Future research is needed to determine whether urate-lowering therapy has beneficial effects for reducing the incidence of CI-AKI and in-hospital adverse events.

Effect of Danlou Tablet (丹蒌片) on peri-procedural myocardial injury among patients undergoing percutaneous coronary intervention for non-ST elevation acute coronary syndrome: A study protocol of a multicenter, randomized, controlled trial

BackgroundIt has been shown that administration of statins reduced the risk of peri-procedural myocardial damage. However, it remains unclear whether Chinese medicine Danlou Tablet (丹蒌片), similar to statins, may protect patients undergoing percutaneous coronary intervention (PCI) from peri-procedural myocardial damage.ObjectiveTo demonstrate the hypothesis whether treatment with Danlou Tablet would improve clinical outcome in patients undergoing selective PCI with non-ST elevation acute coronary syndrome (NSTE-ACS) in China.MethodsApproximately 220 patients with unstable angina or non-ST-segment elevation myocardial infarction undergoing PCI will be enrolled and randomized to Danlou Tablet treatment (4.5 g/day for 2 days before intervention, with a further 4.5 g/day for 90 days thereafter) or placebo. All patients will not receive Danlou Tablet before procedure. The primary end point is to evaluate the incidence of cardiac death, myocardial infarction or unplanned re-hospitalization and revascularization after 30 days in patients undergoing selective PCI treated with Danlou Tablet compared with placebo. Secondary endpoints include the incidence of peri-procedural myocardial injury, 3-month clinical outcomes, the quality of life and Chinese medicine syndromes assessment.ConclusionThis study protocol will provide important evidence of Danlou Tablet treatment on the peri-procedural myocardial injury in patients with NSTE-ACS undergoing selective PCI, which may support a strategy of routine Danlou Tablet therapy to improve the clinical outcomes.

Gastroprotective Effects of Astragaloside IV against Acute Gastric Lesion in Rats

Background Protection of the gastric mucosa from acute lesions induced by various irritants is a pertinent issue in the field of critical care medicine. In this study, we investigated the gastroprotective effects of astragaloside IV on acute gastric lesions in rats under stressful conditions. Methods Rats were randomized into six groups. Group 1 and 2 received 10% Tween 80 (vehicle). Group 3 received 20 mg/kg of omeprazole, a proton pump inhibitor. Groups 4, 5 and 6 received astragaloside IV at concentration of 1, 10, and 50 mg/kg, respectively. As a means to induce gastric lesions, Groups 2–6 were subjected to water immersion and restraint stress for 12 hours after treatment. Results Our present studies show that compared to rats in group 2, treatment with 1 to 50 mg/kg astragaloside IV significantly decreased the size of gastric lesions, MDA, TNFα and MCP1 levels, in addition to normalizing gastric pH, gastric mucus and SOD levels (P<0.05). Histomorphological examination confirmed that treatment with astragaloside IV elicited a dosage-dependent protective effect on the gastric mucosa. Furthermore, pretreatment with astragaloside IV resulted in significant elevations in HSP70 and reduction in Bax, along with over-expression of PLCγ response level, which was further confirmed via immunohistochemical analysis. Conclusions The acute gastric lesions induced are attenuated by pretreatment with astragaloside IV which is possibly due to the enhancing of the expression of HSP70 with concomitant antioxidant, anti-inflammatory and anti-apoptotic capacity.

Shenzhu Guanxin Recipe Granules (参术冠心方颗粒) for Improving Exercise Tolerance in Patients with Stable Angina (SERIES Trial): A Protocol of Multicenter, Randomized, Double-Blind, Placebo Parallel Controlled Clinical Trial

BackgroundMany patients with chronic angina experience anginal episodes despite successful recanalization, antianginal and antiischemic medications. Empirical observations suggested that Shenzhu Guanxin Recipe Granules (参术冠心方颗粒, SGR), a Chinese herbal compound, exerted potential impacts on increased treadmill exercise performance and angina relieve. However, there has been no systematic study to clarify the impact of SGR on exercise tolerance in patients with stable angina. The SERIES (ShEnzhu guanxin Recipe for Improving Exercise tolerance in patients with Stable angina) trial is designed to determine the effects of SGR on exercise duration, electrocardiographic (ECG) evidence of myocardial ischemia, and incidence of major adverse cardiac events (MACE) in stable anginal patients.MethodsA total of 184 eligible patients with stable angina will be randomly assigned to receive placebo or SGR (10 g/day for 12 weeks) in a 1:1 ratio. The primary outcome will be the change from baseline in total exercise tolerance duration, time to onset of angina and ECG ischemia during exercise treadmill testing performed over a 12-week study period. The secondary outcome will include ECG measures, the occurrence and composite of MACE and the Seattle Angina Questionnaire score. Moreover, the coronary microcirculation will be evaluated to explore the possible effects in response to treatment of SGR. After the procedure, all participants will be followed up by interview at 3 and 6 months, enquiring about any cardiac events, hospitalizations, cardiac functional level and medication usage. Additionally, the occurrence of adverse events will be evaluated at each follow-up.DiscussionThis study may provide novel evidence on the efficacy of SGR in improving exercise tolerance and potentially reducing clinical adverse events. (Trial registration No. ChiCTR-TRC-14004504)

Nanoparticle-mediated delivery of Tanshinone IIA reduces adverse cardiac remodeling following myocardial infarctions in a mice model: role of NF-κB pathway

Abstract Our previous works have shown that tanshinone IIA inhibited maladaptive extracellular matrix remodeling in cardiac fibroblasts implicating its potential role in treating of pathologic cardiac remodeling. However, the intrinsically poor solubility and bioavailability of tanshinone IIA hindered its clinical application. Here we develop monomethoxy-poly (ethylene glycol)-poly (lactic acid)-D-α-Tocopheryl polyethylene glycol 1000 succinate (mPEG-PLA-TPGS) nanoparticle incorporating tanshinone IIA (tanshinone IIA-NPs) and study its efficacy in post-infarction left ventricular (LV) remodeling. Male C57BL/6 mice underwent left coronary artery ligation followed by subsequent intravenously injected tanshinone IIA-NPs therapy for 5 consecutive days. Treatment with tanshinone IIA-NP improved cardiac function, limited infarct expansion, and prevented left ventricle dilation at 4 weeks post-MI. Furthermore, cardiomyocytes inflammation, apoptosis and myocardial fibrosis were significantly attenuated in tanshinone IIA-NP treated mice. These effects also correlated with inhibition of IκB protein phosphorylation and NF-κB activation, leading to suppression of proinflammatory cytokine expression. Together, these results demonstrate tanshinone IIA-NP attenuated adverse cardiac remodeling and dysfunction mediated through prevention of IκB phosphorylation and NF-κB activation. Tanshinone IIA-NP is a novel approach to treat myocardial IR injury in patients with MI.

Effectiveness of Tongguan capsules on restenosis after coronary stent implantation: a randomised controlled trial

Abstract Background Although percutaneous coronary intervention (PCI) has become a widely used therapeutic procedure for coronary artery disease, stent restenosis limits the benefits of this revascularisation. The question of how to prevent such events remains unresolved. Empirical evidence suggests that Tongguan capsules, a patented Chinese Medicine, can decrease frequency and duration of angina pectoris attacks; however, evidence supporting its efficacy on restenosis remains inadequate. We aimed to determine whether Tongguan capsules could reduce restenosis incidence in patients after successful stent implantation. Methods In this single-centre, open-label randomised controlled trial, patients undergoing percutaneous coronary stent deployment who were aged 18–80 years were enrolled from Guangdong Provincial Hospital of Chinese Medicine and randomly assigned (1:1) to receive either Tongguan capsules for 3 months (4·5 g/day; Tongguan group) or nothing (control group). All patients received standard anti-platelet, anti-coagulation, and lipid-decreasing treatments, concurrently. The Clinical Research Centre from Guangzhou University of Chinese Medicine generated separate randomisation schedules using a random number generator. All attending physicians, investigators, and the biostatisticians performing the analysis were masked to treatment assignment. The primary clinical endpoint was the 12-month incidence of any major adverse cardiovascular event (defined as cardiac death, myocardial infarction, or recurrence of symptoms requiring additional revascularisation). The primary angiographic endpoint was restenosis incidence at 6 months. The Clinical Research Ethical Committee at Guangdong Provincial Hospital of Chinese Medicine approved the research protocol (Z2017008-01). This trial was registered in ChiCTR (ChiCTR-IIR-17011407). All participants provided written informed consent before enrolment. Findings We enrolled 326 patients between Aug 1, 2014, and Dec 1, 2015. Of these patients, 163 were randomly assigned to the Tongguan group and 163 to the control group. Four patients were excluded leaving 322 patients (160 in the Tongguan group and 162 in the control group) for analysis. Compared with the control group, 12-month incidence of major adverse cardiovascular events was reduced in patients treated with Tongguan capsules (12·5% [20 of 160] vs 23·5% [38 of 162], p Interpretation Although not significant, there was a trend towards a reduction in restenosis and therefore more research is needed to establish whether Tongguan capsules can improve clinical outcomes. Further higher quality and more rigorous randomised trials with larger sample size are needed to attain more robust clinical evidences of Tongguan capsules. Funding National Science Foundation (81473471, 81202782, 81573708).