Intermittent hypoxia reduces infarct size in rats with acute myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: To determine whether intermittent hypoxia (IH) can reduce the infarct size (IS) after acute myocardial infarction (AMI) in rats. METHODS: Articles were identified in PubMed, EMBASE and the Web of Science and were included if they evaluated the effect of IH on the changes in the infarcted area after AMI in rats. RESULTS: A preliminary search identified 3633 articles and 29 data sets from 23 articles (12 in vivo, 16 in vitro). The IS decreased after AMI in IH rats both in vitro (SMD -1.46, 95% CI [- 2.37, - 0.55]; I2 = 85.6%, P = 0.000) and in vivo (SMD -1.43, 95% CI [- 2.05, - 0.82], I2 = 73.6%, P = 0.000). Sensitivity analysis indicated that IH had a strong protective effect against myocardial infarction, and the hypoxia concentration was significantly correlated with the change in IS after AMI. CONCLUSION: IH can reduce IS after AMI in rats. This effect of IH may be related to the dose of hypoxia, and the oxygen concentration may be one of the most important influencing factors.

Two new C19-diterpenoid alkaloids from Aconitum tsaii.

Two new C19-diterpenoid alkaloids, 14-benzoylliljestrandisine (1) and 14-anisoylliljestrandisine (2), were isolated from the roots of Aconitum tsaii. Their structures were elucidated by different spectroscopic (IR, UV, 1D and 2D NMR) and mass-spectrometric techniques.

Ghrelin inhibits atherosclerotic plaque angiogenesis and promotes plaque stability in a rabbit atherosclerotic model.

Intraplaque angiogenesis associates with the instability of atherosclerotic plaques. In the present study, we investigated the effects of ghrelin on intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis. The rabbits were randomly divided into three groups, namely, the control group, atherosclerotic model group, and ghrelin-treated group, with treatments lasting for 4 weeks. We found that the thickness ratio of the intima to media in rabbits of the ghrelin-treated group was significantly lower than that in rabbits of the atherosclerotic model group. The number of neovessels and the levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) decreased dramatically in rabbits of the ghrelin-treated group compared to those of the atherosclerotic model group. Ghrelin significantly decreased the plaque content of macrophages, matrix metalloproteinase (MMP)-2, and MMP-9, in a rabbit model of atherosclerosis. In addition, the level of the pro-inflammatory factor monocyte chemoattractant protein (MCP)-1 was significantly lower in rabbits of the ghrelin-treated group than in rabbits of the atherosclerotic model group. In summary, ghrelin can inhibit intraplaque angiogenesis and promote plaque stability by down-regulating VEGF and VEGFR2 expression, inhibiting the plaque content of macrophages, and reducing MCP-1 expression at an advanced stage of atherosclerosis in rabbits.

Effectiveness of Ivabradine in Treating Stable Angina Pectoris.

Many studies show that ivabradine is effective for stable angina.This meta-analysis was performed to determine the effect of treatment duration and control group type on ivabradine efficacy in stable angina pectoris.Relevant articles in the English language in the PUBMED and EMBASE databases and related websites were identified by using the search terms "ivabradine," "angina," "randomized controlled trials," and "Iva." The final search date was November 2, 2015.Articles were included if they were published randomized controlled trials that related to ivabradine treatment of stable angina pectoris.Patients with stable angina pectoris were included.The patients were classified according to treatment duration (<3 vs ≥3 months) or type of control group (placebo vs beta-receptor blocker). Angina outcomes were heart rate at rest or peak, exercise duration, and time to angina onset.Seven articles were selected. There were 3747 patients: 2100 and 1647 were in the ivabradine and control groups, respectively. The ivabradine group had significantly longer exercise duration when they had been treated for at least 3 months, but not when treatment time was less than 3 months. Ivabradine significantly improved time to angina onset regardless of treatment duration. Control group type did not influence the effect of exercise duration (significant) or time to angina onset (significant).Compared with beta-blocker and placebo, ivabradine improved exercise duration and time to onset of angina in patients with stable angina. However, its ability to improve exercise duration only became significant after at least 3 months of treatment.

Two new C19-diterpenoid alkaloids from Aconitum straminiflorum.

Two new C19-diterpenoid alkaloids, straconitines A (1) and B (2), were isolated from the roots of Aconitum straminiflorum. Their structures were elucidated as 14-benzoylducloudine D (1) and 6-hydroxy-14-benzoylducloudine D (2) based on spectroscopic analysis, including IR, ESI-MS, HR-ESI-MS, 1D, and 2D NMR.

Bone marrow mesenchymal stromal cells with CD47 high expression via the signal transducer and activators of transcription signaling pathway preventing myocardial fibrosis.

UNLABELLED: This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) in which being over-expressed with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). BiAb was prepared and combined with isolated MSC with CD47 overexpression from male mice and trans-fused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB. This study included five groups. Five weeks after treatment, expression levels of the sex-determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of signal transducer and activators of transcription (STAT) 1 and STAT 3 was detected by Western blot. RESULTS: The highest homing number of MSC was in the CD47 + MSC + BiAb + MB group, second highest in the CD47 + MSC + BiAb group, and lowest in MSC alone. Compared with the Control group, CD47 + MSC + BiAb + MB, CD47 + MSC + BiAb, CD47 + MSC and MSC groups had decreased levels of MMP-9, TIMP-1, STAT 1 and collagen deposition, and increased levels of STAT 3. Up regulated STAT 3 and down regulated TIMP-1 were significantly different in CD47 + MSC + BiAb + MB compared with CD47 + MSC or CD47 + MSC + BiAb. CONCLUSION: CD47 can enhance the homing rate and repairing efficacy of MSC. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway.

Ghrelin ameliorates impaired angiogenesis of ischemic myocardium through GHSR1a-mediated AMPK/eNOS signal pathway in diabetic rats.

OBJECTIVES: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), has been found to stimulate angiogenesis in vivo and in vitro. However, the effect and the corresponding mechanisms of ghrelin on impaired myocardial angiogenesis in diabetic and myocardial infarction (MI) rat model are still unknown. METHODS: In the present study, adult SD rats were randomly divided into 4 groups: control, DM, DM+ghrelin, DM+ghrelin+[D-Lys3]-GHRP-6 groups. DM was induced by streptozotocin (STZ) 60 mg/kg body weight. 12 weeks post STZ injection all groups were subjected to MI, which was induced by ligation left anterior descending artery (LAD). Ghrelin and [D-Lys3]-GHRP-6 were administered via intraperitoneal injection at the doses 200 µg/kg and 50mg/kg for 4 weeks, respectively. Left ventricular function, microvascular density (MVD), myocardial infarct size, the expression of hypoxia-inducible factor (HIF1α), vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1), AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation were examined. RESULTS: Compared with the DM group, left ventricular ejection fraction (LVEF), fractional shortening (FS), and MVD were increased, whereas myocardial infarct size decreased remarkably in DM+ghrelin group. For the mechanism study, we found that ghrelin promoted the HIF1α, VEGF, Flk-1 and Flt-1 expression, AMPK and eNOS phosphorylation in diabetic rats. However, the above biochemical events in ghrelin treated diabetic rats were completely inhibited by GHSR-1a blocker [D-Lys3]-GHRP-6. CONCLUSIONS: These results suggest that administration of ghrelin ameliorates impaired angiogenesis in diabetic MI rats. And these beneficial effects derive from regulating GHSR1a-mediated AMPK/eNOS signal pathway by upregulating of HIF1α, VEGF and its receptors Flk-1, Flt-1 expressions.

Octanoylated ghrelin attenuates angiogenesis induced by oxLDL in human coronary artery endothelial cells via the GHSR1a-mediated NF-κB pathway.

OBJECTIVE: Low concentrations of oxidized low-density lipoprotein (oxLDL) promote the in vitro angiogenesis of endothelial cells and play an important role in plaque angiogenesis, which may cause plaque vulnerability and enhance the risk of intravascular thrombosis. The aim of this research was to investigate the effects of octanoylated ghrelin on oxLDL-induced angiogenesis and the underlying molecular mechanisms involved in this process. MATERIALS/METHODS: Human coronary artery endothelial cells (HCAECs) were incubated with 5 µg/ml oxLDL and treated with various concentrations of octanoylated ghrelin (10(-9)-10(-6)M) with or without inhibitors for 24h. Cell proliferation, migration, and in vitro angiogenesis were analyzed by bromodeoxyuridine (BrdU) staining and BrdU enzyme-linked immunosorbent assay (ELISA), transwell assay, and tube formation on Matrigel, respectively. NF-κB (nuclear factor κB) expression was determined by Western-blot analysis. RESULTS: Treatment with oxLDL at 5 µg/ml enhanced the proliferation, migration and tube formation of HCAECs. In contrast, pretreatment with octanoylated ghrelin significantly attenuated in vitro angiogenesis in oxLDL-induced HCAECs. In addition, Western blot analysis indicated that NF-κB expression was increased after oxLDL treatment, and that this effect was significantly reversed by pretreatment with octanoylated ghrelin. However, the NF-κB inhibitor PDTC or the GHSR1a inhibitor [D-Lys3]-GHRP-6 abolished the effects of octanoylated ghrelin on the inhibition of angiogenesis and NF-κB p65 expression induced by oxLDL. CONCLUSIONS: These findings suggest that octanoylated ghrelin attenuates angiogenesis induced by oxLDL in HCAECs via the inhibition of GHSR1a-mediated NF-κB pathway. Furthermore, octanoylated ghrelin may promote the stability of vulnerable plaques by inhibiting plaque angiogenesis.

[Effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction].

OBJECTIVE: To investigate the effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction (MI). METHODS: Adult male SD rats were divided into six groups (n = 20 each group): control, diabetes mellitus (DM), MI, DM+MI, DM+MI+ghrelin, DM+MI+ghrelin+D-Lys3-GHRP-6 (GHSR1a inhibitor). DM was induced by streptozotocin (STZ, 60 mg/kg), 3 months later, MI was induced by left anterior descending artery ligation in DM rats. DM+MI+ghrelin group received ghrelin 200 µg×kg(-1)×d(-1) and DM+MI+ghrelin+D-Lys3-GHRP-6 group received ghrelin 200 µg×kg(-1)×d(-1) and D-Lys3-GHRP-6 50 mg×kg(-1)×d(-1) for 4 weeks. Then, cardiac function was measured by echocardiography, microvascular density (MVD) was measured by CD34 immunohistochemistry, myocardial infarct size was determined by Masson staining, the mRNA and protein expressions of vascular endothelial growth factor (VEGF) and receptors Flk-1, Flt-1 were detected by real-time PCR and Western-blot, respectively. RESULTS: Compared with MI group, MVD (15.3 ± 1.0 vs.20.7 ± 1.6, P < 0.05), left ventricular ejection fraction (LVEF) ((64.2 ± 3.4)% vs. (81.3 ± 3.8)%, P < 0.01), left ventricular fractional shortening (LVFS) ((31.7 ± 1.1)% vs. (48.8 ± 3.3)%, P < 0.01) and the mRNA and protein expression of VEGF, Flk-1 and Flt-1 (P < 0.01) were reduced, while myocardial infarct size ((55.8 ± 3.1)% vs. (35.7 ± 2.5)%, P < 0.01) was increased in DM+MI group. These effects were partly reversed in DM+MI+ghrelin group and the beneficial effects of ghrelin were partly abolished by D-Lys3-GHRP-6 (all P < 0.05). CONCLUSIONS: Our results demonstrate that ghrelin could improve microvascular density, cardiac function, and reduce myocardial infarct size of diabetic rats with myocardial infarction via modulating GHSR1a-mediated expressions of VEGF, Flk-1 and Flt-1.

Emodin protects against diabetic cardiomyopathy by regulating the AKT/GSK-3ß signaling pathway in the rat model.

Diabetes mellitus (DM) has been recognized as a major health problem. Emodin (Emo) has been reported to exhibit protective effects against diabetic nephropathy. However, little has been known about the effect of Emo on diabetic cardiomyopathy (DCM). A type 2 DM model was induced in rats by low dose streptozotocin (STZ) combined with high energy intake. We found that Emo-treated groups displayed significantly higher body weight (BW) and lower heart weight (HW)/BW. Furthermore, Emo could significantly decrease blood glucose, total cholesterol (TG) levels, and triglyceride (TC) levels in diabetic rats. Moreover, the Emo-treated group showed a marked increase in heart rate (HR) and showed lower left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular posterior wall thickness (LWPWT), and interventricular septal diastolic wall thickness (IVSD). Emo induced a significant increase in phosphorylation of Akt and GSK-3ß in myocardium. These results suggest that Emo may have great therapeutic potential in the treatment of DCM by Akt/GSK-3ß signaling pathway.

Association of circulating endothelial progenitor cells (CD14+-EPC) with renal function in patients with coronary artery disease.

BACKGROUND: The relationships between the endothelial progenitor cells (EPCs)-CD34(+) and CD14(+) and coronary artery disease (CAD) were reported and the association of CD34(+) cells with renal function was studied previously. Another kind EPC-CD14(+) cell and its association with renal function in patients with CAD have not been reported yet. Our aim was to assess CD14(+) cell counts versus renal function in CAD. METHODS AND RESULTS: We studied 242 patients with severe angiographic CAD and 30 healthy control participants. The CD14(+) cells were enumerated by flow cytometry. With lowering glomerular filtration rate (GFR), CD14(+) cell numbers (percentage of lymphocytes, median and interquartile range) decreased: 0.04 (0.03-0.06), 0.03 (0.02-0.05), 0.02 (0.01-0.03) for estimated glomerular filtration rate (eGFR) ≥90, 60 to 89, and 30 to 89 mL/min per 1.73 m(2), respectively (P < .001 for trend). The CD14(+) cell counts correlated with eGFR (r = .27, P = .03). By multivariate liner regression analysis, the difference remains significant (P = .02). CONCLUSIONS: The CD14(+) cell depletion is associated with renal dysfunction in CAD.

Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells.

OBJECTIVE: The purpose of this research was to investigate the effects of ghrelin on circulating endothelial progenitor cells (EPC) directional migration and its underlying molecular mechanisms involved in this process. MATERIALS/METHODS: EPC were isolated from bone marrow of SD rats by using Percoll density gradient centrifugation, and characterized by double positive for acLDL-Dil uptake and FITC-UEA-1 binding and immunocytochemistry for CD34, CD133, vWF and Flk-1. EPC were treated with different concentrations of ghrelin (10(-9)~10(-6)M) with or without GHSR1a inhibitor [D-Lys3]-GHRP-6, PI3K inhibitor LY294002 and endothelial nitric oxide synthase (eNOS) inhibitor L-NAME, migration of EPC was detected by transwell assay, levels of phosphorylated and total Akt and eNOS were determined by Western-blot analysis and Nitric Oxide (NO) production was measured by Griess assay, respectively. RESULTS: EPC were successfully obtained by Percoll density gradient centrifugation and ghrelin at 10(-8)M~10(-7)M promoted EPC migration. Ghrelin-induced EPC migration was accompanied by phosphorylation of Akt and eNOS, as well as an increase in NO production. These biochemical events and EPC directional migration induced by ghrelin were completely inhibited by GHSR-1a blocker [D-Lys3]-GHRP-6. PI3K inhibitor LY294002 attenuated ghrelin-induced EPC migration, phosphorylation of Akt and eNOS, and NO production. eNOS inhibitor L-NAME blocked ghrelin-induced EPC migration, phosphorylation of eNOS, and NO production, but had no effect on Akt phosphorylation. CONCLUSIONS: These findings suggest that ghrelin stimulates EPC directional migration via GHSR1a-mediated PI3K/Akt/eNOS/NO signal pathway. It indicates that ghrelin may be used as a therapeutic strategy to treat ischemic diseases by promoting EPC directional migration.

[Ghrelin stimulates in vitro angiogenic capacity of rat cardiac microvascular endothelial cells].

OBJECTIVE: To clarify whether ghrelin could promote in vitro rat cardiac microvascular endothelial cells (CMECs) angiogenesis and related mechanisms. METHODS: CMECs were isolated from myocardial tissue of adult male SD rats and characterized by the immunocytochemistry staining with Factor VIII and the capacity of in vitro capillary tube-like formation. The mRNAs and protein expressions of ghrelin and its receptor (growth hormone secretagogue receptor, GHS-R) of CMECs were determined by RT-PCR, Immunofluorescence, ELISA and Western blot. Proliferation, migration and in vitro angiogenesis as well as ERK2 phosphorylation of CMECs were tested in the presence of ghrelin (10(-9) - 10(-7) mol/L) with or without pretreatment with specific MAPK/ERK2 inhibitor PD98059. RESULTS: Purity of CMECs characterized by immunocytochemistry staining with Factor VIII was about 95%, and the cells showed a high ability to form the capillary tube-like structures on Matrigel. Ghrelin and GHS-R were constitutively expressed in CMECs. Proliferation, migration and in vitro angiogenesis capacities of CMECs (72.20 ± 5.72 vs. 28.60 ± 5.13, P < 0.001; 71.00 ± 7.78 vs. 28.60 ± 5.13, P < 0.001) as well as ERK2 phosphorylation (0.92 ± 0.13 vs. 0.29 ± 0.04, P < 0.001; 1.15 ± 0.16 vs. 0.29 ± 0.04, P < 0.001) were significantly enhanced by exogenous ghrelin (10(-8) - 10(-7) mol/L). PD98059 abolished ghrelin-induced ERK2 phosphorylation and in vitro angiogenesis. CONCLUSIONS: Ghrelin and its receptor are expressed in CMECs and ghrelin could stimulate CMECs in vitro angiogenesis through activation of MAPK/ERK2 signaling pathway.

Association between FTO gene polymorphism and cancer risk: evidence from 16,277 cases and 31,153 controls.

A recent genome-wide association study showed that the rs9939609 polymorphism in the fat mass and obesity-associated (FTO) gene was associated with body mass index (BMI)/obesity in Europeans. Subsequently, several studies have investigated the association between FTO polymorphism and cancer risk. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the association between FTO polymorphism and cancer risk. Published literature from PubMed and Embase databases were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed-effects model. A total of 13 studies involving 16,277 cases and 31,153 controls were identified. The results suggested that FTO rs9939609 polymorphism was not significantly associated with the increased risk of cancer (OR = 1.01, 95 %CI 0.98-1.04), with the exception that a statistically significant association was found for pancreatic cancer (OR = 1.10, 95 %CI 1.03-1.19). No publication bias was detected (Begg's test: P = 0.760; Egger's test: P = 0.553). Our meta-analysis indicated that there was no association between FTO rs9939609 polymorphism and the increased risk of cancer, although this polymorphism was marginally associated with pancreatic cancer. However, the conclusion should be made with caution since most included studies did not take BMI/obesity into account.

Ghrelin stimulates angiogenesis via GHSR1a-dependent MEK/ERK and PI3K/Akt signal pathways in rat cardiac microvascular endothelial cells.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), is thought to exert a protective effect on the cardiovascular system, specifically by promoting vascular endothelial cell function such as cell proliferation, migration, survival and angiogenesis. However, the effect of ghrelin on angiogenesis and the corresponding mechanisms have not yet been extensively studied in cardiac microvascular endothelial cells (CMECs) isolated from left ventricular myocardium of adult Sprague-Dawley (SD) rats. In our study, we found that ghrelin and GHSR are constitutively expressed in CMECs. Ghrelin significantly increases CMECs proliferation, migration, and in vitro angiogenesis. The ghrelin-induced angiogenic process was accompanied by phosphorylation of ERK and Akt. MEK inhibitor PD98059 abolished ghrelin-induced phosphorylation of ERK, but had no effect on Akt phosphorylation. PI3K inhibitor LY294002 abolished ghrelin-induced phosphorylation of Akt, but had no effect on ERK phosphorylation. Ghrelin-induced angiogenesis was partially blocked by treatment with PD98059 or LY294002. In addition, this angiogenic effect was almost completely inhibited by PD98059+LY294002. Pretreatment with GHSR1a blocker [D-Lys3]-GHRP-6 abolished ghrelin-induced phosphorylation of ERK, Akt and in vitro angiogenesis. In conclusion, this is the first demonstration that ghrelin stimulates CMECs angiogenesis through GHSR1a-mediated MEK/ERK and PI3K/Akt signal pathways, indicating that two pathways are required for full angiogenic activity of ghrelin. This study suggests that ghrelin may play an important role in myocardial angiogenesis.

Analysis of the correlation between non-high density lipoprotein cholesterol and coronary heart disease in elderly Chinese.

OBJECTIVE: In the aged population, serum cholesterol is directly correlated with coronary heart disease (CHD) risk. We aimed to investigate the correlation between non-high density lipoprotein cholesterol (non-HDL-C) level and CHD and coronary lesions in an aged population. METHODS: 1,272 cases of old patients who were more than 65 years old and accepted for coronary angiography were analyzed retrospectively. Based on the result of coronary angiography, the patients were divided into control group and CHD group. Further, 767 CHD patients were divided into subgroups according to the number of branches with pathological changes and Gensini score. Serum TC, HDL-C, LDL-C and TG were assayed to measure the level of non-HDL-C. The differences in non-HDL-C among groups were compared, and the correlation between non-HDL-C and coronary artery disease degree was also analyzed. RESULTS: The non-HDL-C level in the CHD group was significantly higher than that in the control group (p < 0.01). Further, the serum non-HDL-C showed an increasing tendency accompanied by the increase in branches with lesions. Compared with patients with single or double coronary artery branches lesions, the non-HDL-C in those with multiple lesions in branches was significantly increased (p < 0.01, p < 0.05). With the aggravation of coronary artery stenosis, the serum non-HDL-C level was gradually increased. The most significant increase was observed in the group with Gensini score of more than 40. There was a significant difference between Gensini score > 40 group and Gensini score of 20-40 group and Gensini score < 20 group, respectively (p < 0.05, p < 0.01). Meanwhile, there were significant positive correlations between the serum non-HDL-C level and coronary lesions area and severity (r = 0.147, p < 0.01; r = 0.152, p < 0.01). CONCLUSION: In conclusion, serum non-HDL-C was closely associated with development of CHD and coronary artery lesions severity.

Bone marrow mesenchymal stromal cells with support of bispecific antibody and ultrasound-mediated microbubbles prevent myocardial fibrosis via the signal transducer and activators of transcription signaling pathway.

BACKGROUND AIMS: This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). METHODS: BiAb (anti-CD29 × anti-myosin light chain antibody; AMLCA) was prepared and combined with isolated MSC from male mice and transfused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB (MSC + BiAb + MB). This study included seven groups: MSC + BiAb + MB; MSC; BiAb; MB; MSC + BiAb; untreated; and control. Five weeks after treatment, expression levels of the sex-determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). Collagen distribution was observed using Sirius Red staining. The protein expression of signal transducer and activators of transcription (STAT)1 and STAT3 was detected by Western blot. RESULTS: The highest homing number of MSC was in the MSC + BiAb + MB group, second highest in the MSC + BiAb group, and lowest in MSC alone. Compared with the untreated group, MSC + BiAb + MB, MSC + BiAb and MSC groups had decreased levels of MMP-9, TIMP-1, STAT1 and collagen deposition, and increased levels of STAT3. Upregulated STAT3 and downregulated TIMP-1 were significantly different in MSC + BiAb + MB compared with MSC alone or MSC + BiAb. CONCLUSIONS: The homing rate and repairing efficacy of MSC improved with treatment utilizing a combination of BiAb and MB. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway.

Suppression of NHE1 by small interfering RNA inhibits HIF-1α-induced angiogenesis in vitro via modulation of calpain activity.

Hypoxia-inducible factor-1 (HIF-1) orchestrates angiogenesis under hypoxic conditions mainly due to increased expression of such target genes as vascular endothelial growth factor (VEGF). Na+/H+exchanger-1 (NHE1), a potential HIF target gene product, plays a pivotal role in proliferation, survival, migration, adhesion and so on. However, it is unknown whether NHE1 is involved in HIF-1α-induced angiogenesis. This present study demonstrated that the expression of NHE1 was much higher in human umbilical vein endothelial cells (HUVECs) infected with adenovirus encoding HIF-1α (rAd-HIF) than with vacuum adenovirus (vAd). HIF-1α also increased the expression of VEGF, the expression and activity of calpains, and the intracellular pH. Moreover, small interfering RNA targeting NHE1 (NHE1 siRNA) dramatically decreased the expression of NHE1 and thus lowered the intracellular pH, and it also attenuated the protein expression of calpain-2 but not calpain-1, resulting in the lower calpain activity. Furthermore, HIF-1α enhanced the proliferation, migration and Matrigel tube formation, which were inhibited by NHE1 siRNA. Finally, the inhibitory effect of NHE1 siRNA was reversed by VEGF and the reversibility of the later was abrogated by the calpain inhibitor ALLM. In conclusion, the findings have revealed that NHE1 might participate in HIF-1-induced angiogenesis due, at least in part, to the alteration of the calpain activity, suggesting that NHE1 as well as calpains might represent a potential target of controlling angiogenesis in response to the hypoxic stress under various pathological conditions.

Procollagen III N-terminal peptide predicts short-term prognosis and cardiac remodeling in coronary heart disease patients with metabolic syndrome.

INTRODUCTION: Many patients with coronary heart disease (CHD) also have metabolic syndrome (MS); however, little is known about the condition of cardiovascular remodeling in these patients. The objective of this study to explore the role of plasma procollagen III N-terminal peptide (PIIINP) in predicting the prognosis and cardiac remodeling in patients with CHD with MS. METHODS: One hundred eight patients were classified into high and low PIIINP groups according to the median value of plasma PIIINP. Cardiovascular examinations including echocardiogram, carotid color ultrasound examination, coronary angiography and the 6-minute walking test (6MWT) were performed before and after a 1-year follow-up. Readmission for cardiac and cerebrovascular events was assessed during the follow-up period. RESULTS: Plasma PIIINP level was significantly correlated with age, high-sensitivity C-reactive protein (hs-CRP) and body mass index in a multiple stepwise regression model. There was a positive correlation between the LnPIIINP and an increased left ventricular mass index in partial correlation analysis. The Cox proportional hazard model analysis indicated that the level of PIIINP, left ventricular ejection fraction and hs-CRP were independent predictors of readmission owing to cardiac and cerebrovascular events during the follow-up. A PIIINP value of 4.0 µg/L was the best threshold value for determining the need for readmission. CONCLUSIONS: PIIINP levels rise with increases in age, hs-CRP and body mass index in patients with CHD with MS, and a high level of PIIINP indicates recent deterioration of cardiac remodeling and exercise tolerance and a poor prognosis.

Safety and effectiveness of percutaneous coronary intervention (PCI) in elderly patients. a 5-year consecutive study of 201 cases with PCI.

The study objectives were to evaluate the safety and effectiveness of PCI in the elderly. The 201 cases with PCI were divided into the younger group (<60-year-old group, 33 cases), the old group (60- to 74-year-old group, 92 cases) and the very old group (75- to 89-year-old group, 76 cases). We found that the incidence of 2-vessel disease, multi-vessel disease and complex lesions in the old and very old group was more frequent than that in the younger group (p<0.05, p<0.05, p<0.05). From the younger group to the very old group, the Gensini score increases significantly (40.50 vs. 42.00 vs. 45.25, p<0.05, p<0.01, p<0.01). The immediate success rate of PCI was 99.01% (199/201), and no significant difference was found in the three age groups. The complete revascularization in the very old group was much less than that in the old and younger groups. Logistic regression showed that only the incomplete revascularization was the independent risk factor of adverse events (odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.37-5.72). We conclude that in the elderly patients with favorable tolerance of PCI, PCI immediate success rate was similar to that of the young patients, suggesting that complete revascularization of the very old patients might improve the prognosis and reduce the incidence of cardiac events.