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Zhaohui Hu,
Jie Zhang,
Aili Guan,
Hui Gong,
Ming Yang,
Guoping Zhang,
Jianguo Jia, Hong Ma,
Chunjie Yang,
Junbo Ge,
Yunzeng Zou
[show abstract]
[hide abstract]
ABSTRACT: Granulocyte-colony stimulating factor (G-CSF) has been reported to improve the function of infarcted heart, but its effects on atherosclerosis are unclear. Here we examined the effects and the potential mechanisms in the high-fat diet rabbit model. Six-month-old male New Zealand white rabbits, fed a high-cholesterol diet or a normal diet for 10 weeks, were treated with vehicle or G-CSF. G-CSF increased lesion area in the thoracic aorta and the plasma levels of total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) at the early phase in the high-fat diet group. High-fat diet-induced arterial endothelium damage and apoptosis were greatly aggravated by G-CSF treatment. In vivo, G-CSF impaired apoptosis induced by oxidized low density lipoprotein (OX-LDL) but it had little effect on cultured endothelial cells (ECs) with vehicle treatment. Further research revealed that G-CSF promoted the upregulation of endothelin-1 (ET-1) and the downregulation of endothelial nitric oxide synthase (eNOS) of thoracic aortae induced by a high-fat diet. In vitro, the effects of G-CSF on expression of ET-1 and eNOS in cultured ECs were consistent with those in vivo. Our results suggested that G-CSF exacerbates lipid abnormity and endothelium damage in hyperlipidemia rabbits, thereby resulting in the deterioration of atherosclerosis and that the ET-1/eNOS system may regulate the progression.
International Journal of Molecular Sciences 01/2013; 14(3):4805-16. · 2.60 Impact Factor
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Jian Wu,
Jieyun You,
Lei Li, Hong Ma,
Jianguo Jia,
Guoliang Jiang,
Zhidan Chen,
Yong Ye,
Hui Gong,
Liping Bu,
Junbo Ge,
Yunzeng Zou
[show abstract]
[hide abstract]
ABSTRACT: Elevation of left ventricular end-systolic pressure (LVESP) and hypertrophic response in mice varies after transverse aorta constriction (TAC). Micromanometric catheterization, conventionally used to select mice with successful TAC, is invasive and nonreusable. We aimed to establish noninvasive imaging protocols for early estimation of successful TAC by ultrasound biomicroscopy (UBM). Out of 55 C57BL/6J mice, we randomly selected 45 as TAC group and 10 as controls. UMB was performed before TAC and, at day 3 and day 14, after TAC. In all mice, LVESP was measured with a Millar conductance catheter at day 14. With LVESP ≥ 150 mm Hg set as indicator of successful TAC (TAC+) and LVESP < 150 mm Hg as unsuccessful (TAC-), receiver operating characteristic curve analysis demonstrated that postoperative inner diameter at aortic banding site (IDb), peak flow velocity at aortic banding site (PVb) and peak flow velocity of right/left common carotid artery (PVr/l) at day 3 served as most effective predictors for LVESP at day 14 (area under curve = 0.9016, 0.9143, 0.8254, respectively. p < 0.01 for all). Among all UBM parameters at day 3, IDb, PVb, right common carotid artery peak flow velocity (PVr) and PVr/l correlated best with LVESP at day 14 (R(2) = 0.5740, 0.6549, 0.5208, 0.2274, respectively. p < 0.01 for all). Furthermore, IDb, PVb, and PVr/l at day 3 most effectively predict long-term cardiac hypertrophy, using the cut-off values of 0.45 mm, 2698.00 mm/s, 3.08, respectively. UBM can be a noninvasive and effective option for early prediction of successful TAC.
Ultrasound in medicine & biology 03/2012; 38(6):1030-9. · 2.02 Impact Factor
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Hong Ma,
Hui Gong,
Zhidan Chen,
Yanyan Liang,
Jie Yuan,
Guoping Zhang,
Jian Wu,
Yong Ye,
Chunjie Yang,
Akira Nakai,
Issei Komuro,
Junbo Ge,
Yunzeng Zou
[show abstract]
[hide abstract]
ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) has been shown to be cardio-protective against ischemia through activating Jak2/Stat3 pathway, however, the mechanism is unclear. Heat shock transcription factor 1 (HSF1), a definite endogenous protective protein in cardiomyocytes, may interact with Stat family under stress conditions. We hypothesized that G-CSF could induce cardio-protection against ischemia/reperfusion (I/R) through association of HSF1 with Stat3. To test the hypothesis, we built cardiac I/R injury model with HSF1 knockout (KO) mice and wild type (WT) mice by occlusion of the left anterior descending (LAD) coronary artery for 30min and subsequent release of the occlusion for 24h. These mice were administered with G-CSF (100μg/kg/day) or vehicle subcutaneously for 3days before surgery. As expected, G-CSF induced significant cardio-protections against I/R injury, characterized by higher ejection fraction (EF%), lower left ventricular end diastolic pressure (LVEDP), increased dp/dt value and decreased infarct area as compared with the vehicle treatment in WT mice. In HSF1-KO mice, however, these cardio-protections induced by G-CSF were greatly attenuated. Inhibition of oxidative stress-induced cardiomyocyte apoptosis by G-CSF also disappeared due to the deficiency of HSF1 in vitro and in vivo. Furthermore, G-CSF increased the phosphorylation and the association of Stat3 with HSF1, which enhanced transcriptional activity of HSF1. Inhibition of either Stat3 or HSF1 by pharmacological agents suppressed G-CSF-induced association of the two proteins and anti-apoptotic effect on cardiomyocytes. Our data suggest that G-CSF stimulates phosphorylation and association of Stat3 with HSF1 and therefore enhances transcriptional activity of HSF1, leading to the cardio-protection against I/R injury.
Journal of Molecular and Cellular Cardiology 03/2012; 52(6):1282-90. · 5.17 Impact Factor
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Yunzeng Zou,
Yanyan Liang,
Hui Gong,
Ning Zhou, Hong Ma,
Aili Guan,
Aijun Sun,
Ping Wang,
Yuhong Niu,
Hong Jiang,
Hiroyuki Takano,
Haruhiro Toko,
Atsushi Yao,
Hiroshi Takeshima,
Hiroshi Akazawa,
Ichiro Shiojima,
Yuqi Wang,
Issei Komuro,
Junbo Ge
[show abstract]
[hide abstract]
ABSTRACT: Ryanodine receptor type 2 (RyR-2) mediates Ca(2+) release from sarcoplasmic reticulum and contributes to myocardial contractile function. However, the role of RyR-2 in the development of cardiac hypertrophy is not completely understood. Here, mice with or without reduction of RyR-2 gene (RyR-2(+/-) and wild-type, respectively) were analyzed. At baseline, there was no difference in morphology of cardiomyocyte and heart and cardiac contractility between RyR-2(+/-) and wild-type mice, although Ca(2+) release from sarcoplasmic reticulum was impaired in isolated RyR-2(+/-) cardiomyocytes. During a 3-week period of pressure overload, which was induced by constriction of transverse aorta, isolated RyR-2(+/-) cardiomyocytes displayed more reduction of Ca(2+) transient amplitude, rate of an increase in intracellular Ca(2+) concentration during systole, and percentile of fractional shortening, and hearts of RyR-2(+/-) mice displayed less compensated hypertrophy, fibrosis, and contractility; more apoptosis with less autophagy of cardiomyocytes; and similar decrease of angiogenesis as compared with wild-type ones. Moreover, constriction of transverse aorta-induced increases in the activation of calcineurin, extracellular signal-regulated protein kinases, and protein kinase B/Akt but not that of Ca(2+)/calmodulin-dependent protein kinase II, and its downstream targets in the heart of wild-type mice were abolished in the RyR-2(+/-) one, suggesting that RyR-2 is a regulator of calcineurin, extracellular signal-regulated protein kinases, and Akt but not of calmodulin-dependent protein kinase II activation during pressure overload. Taken together, our data indicate that RyR-2 contributes to the development of cardiac hypertrophy and adaptation of cardiac function during pressure overload through regulation of the sarcoplasmic reticulum Ca(2+) release; activation of calcineurin, extracellular signal-regulated protein kinases, and Akt; and cardiomyocyte survival.
Hypertension 12/2011; 58(6):1099-110. · 6.21 Impact Factor
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Yunzeng Zou,
Jiming Li, Hong Ma,
Hong Jiang,
Jie Yuan,
Hui Gong,
Yanyan Liang,
Aili Guan,
Jian Wu,
Lei Li,
Ning Zhou,
Yuhong Niu,
Aijun Sun,
Akira Nakai,
Ping Wang,
Hiroyuki Takano,
Issei Komuro,
Junbo Ge
[show abstract]
[hide abstract]
ABSTRACT: Heat shock transcription factor 1 (HSF1) plays an important role not only in excise-induced cardiac hypertrophy but also in protection against pressure overload-induced cardiac dysfunction. However, the mechanism is not completely understood. We here elucidate the potential mechanisms by which HSF1 protects against pressure overload-induced cardiac remodeling and dysfunction. A sustained constriction of transverse aorta (TAC) was imposed to HSF1 transgenic (TG), knockout (KO) and their littermate wild type (WT) male mice. Four weeks later, adaptive responses to TAC, such as cardiac hypertrophy, contractility and angiogenesis evaluated by echocardiography, catheterization, coronary perfusion pressure and immunohistochemistry were well preserved in TG but not in KO compared with WT mice. An angiogenesis inhibitor TNP-470 abrogated all these adaptive responses in TG mice, while cardiac transfection of VEGF with angiopoietin-1 rescued the broken heart in KO mice. In response to TAC, p53 was downregulated and hypoxia-inducing transcription factor-1 (HIF-1) was upregulated not only in the heart but also in the cultured cardiac endothelial cells (EC) of TG mice as compared to WT mice whereas these changes became opposite in KO mice. A small interfering RNA (siRNA) of HIF-1 but not a p53 gene impaired the adaptive responses of the heart and EC in TG mice, and a siRNA of p53 but not a HIF-1 gene significantly reversed the heart and EC disorders in KO mice after TAC. We conclude that HSF1 promotes cardiac angiogenesis through suppression of p53 and subsequent upregulation of HIF-1 in endothelial cells during chronic pressure overload, leading to the maintenance of cardiac adaptation.
Journal of Molecular and Cellular Cardiology 08/2011; 51(5):821-9. · 5.17 Impact Factor
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Hui Gong, Hong Ma,
Meilan Liu,
Bojiang Zhou,
Guoping Zhang,
Zhidan Chen,
Guoliang Jiang,
Yuan Yan,
Chunjie Yang,
Masato Kanda,
Jian Wu,
Jie Yuan,
Lei Li,
Toshio Nagai,
Issei Komuro,
Junbo Ge,
Yunzeng Zou
[show abstract]
[hide abstract]
ABSTRACT: Urotensin II (UII) induces the development of cardiac remodeling and atherosclerosis by promoting hypertrophy of cardiomyocytes and mitogenesis of fibroblasts and vascular smooth muscle cells. But its effect on cardiac side population cells (CSPs), one of somatic stem cells, is unclear. The present study examined the influences of UII on the differentiation and proliferation of CSPs. CSPs were isolated from neonatal rat hearts by fluorescence-activated cell sorting (FACS) and cultured with or without the presence of UII (10(-8), 10(-7), 10(-6)mol/l). The expressions of α-cardiac myosin heavy chain (α-MHC), α-smooth muscle actin (SMA) and Von Willebrand factor (vWF) mRNAs and proteins were analyzed by reverse transcriptional PCR (RT-PCR) and immunofluorescence to evaluate the differentiation of CSPs into cardiomyocytes, smooth muscle cells and endothelial cells, respectively. The proliferation of CSPs was assessed by Luminescent Cell Viability Assay. The influence of UII on the proliferation of CSPs in vivo was also evaluated by FACS. Our results revealed that UII did inhibit the proliferation of CSPs through up-regulation of phosphorylated c-Jun N-terminal protein kinase (JNK), although it didn't affect the differentiation of cultured CSPs. Experiments in vivo also showed that UII reduced the number of CSPs in mice compared with control group. These data indicate that UII reduces the number of CSPs by inhibiting the proliferation of CSPs possibly through increase of JNK phosphorylation.
Peptides 02/2011; 32(5):1035-41. · 2.43 Impact Factor
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Jian Wu,
Liping Bu,
Hui Gong,
Guoliang Jiang,
Lei Li, Hong Ma,
Ning Zhou,
Li Lin,
Zhidan Chen,
Yong Ye,
Yuhong Niu,
Aijun Sun,
Junbo Ge,
Yunzeng Zou
[show abstract]
[hide abstract]
ABSTRACT: Anesthesia provides sedation and immobility, facilitating echocardiography in mice, but it influences cardiovascular function and therefore outcomes of measurement. This study aimed to determine the effect of the optimal heart rate (HR) and anesthetic timing on echocardiographic reproducibility under isoflurane anesthesia.
Male C57BL/6J mice underwent high-resolution echocardiography with relative fixed HRs and anesthetic timing. The same experiment was repeated once again after 1 week.
Echocardiography was highly reproducible in repeated measurements under low-HR (350-400 beats per minute [bpm]) and high-HR (475-525 bpm) conditions except some M-mode parameters under low-HR conditions. With similar anesthetic timing, mice with a high HR had decreased preload indices and increased ejection phase and Doppler indices. Inversely, when the HR was similar, the echocardiographic results of mice under short anesthetic timing showed little difference from the ones under long anesthetic timing.
This study shows that echocardiographic assessment is greatly reproducible under a high HR. The HR is more important than anesthetic timing for echocardiographic evaluation in mice.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 12/2010; 29(12):1771-8. · 1.25 Impact Factor
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[show abstract]
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ABSTRACT: Optimal timing of cell therapy for myocardial infarction (MI) appears during 5 to 14 days after the infarction. However, the potential mechanism requires further investigation. This work aimed to verify the hypothesis that myocardial stiffness within a propitious time frame might provide a most beneficial physical condition for cell lineage specification in favour of cardiac repair. Serum vascular endothelial growth factor (VEGF) levels and myocardial stiffness of MI mice were consecutively detected. Isolated bone marrow mononuclear cells (BMMNCs) were injected into infarction zone at distinct time-points and cardiac function were measured 2 months after infarction. Polyacrylamide gel substrates with varied stiffness were used to mechanically mimic the infarcted myocardium. BMMNCs were plated on the flexible culture substrates under different concentrations of VEGF. Endothelial progenitor lineage commitment of BMMNCs was verified by immunofluorescent technique and flow cytometry. Our results demonstrated that the optimal timing in terms of improvement of cardiac function occurred during 7 to 14 days after MI, which was consistent with maximized capillary density at this time domains, but not with peak VEGF concentration. Percentage of double-positive cells for DiI-labelled acetylated low-density lipoprotein uptake and fluorescein isothiocyanate (FITC)-UEA-1 (ulex europaeus agglutinin I lectin) binding had no significant differences among the tissue-like stiffness in high concentration VEGF. With the decrease of VEGF concentration, the benefit of 42 kPa stiffness, corresponding to infarcted myocardium at days 7 to 14, gradually occurred and peaked when it was removed from culture medium. Likewise, combined expressions of VEGFR2(+) , CD133(+) and CD45(-) remained the highest level on 42 kPa substrate in conditions of lower concentration VEGF. In conclusion, the optimal efficacy of BMMNCs therapy at 7 to 14 days after MI might result from non-VEGF dependent angiogenesis, and myocardial stiffness at this time domains was more suitable for endothelial progenitor lineage specification of BMMNCs. The results here highlight the need for greater attention to mechanical microenvironments in cell culture and cell therapy.
Journal of Cellular and Molecular Medicine 11/2010; 15(10):2245-61. · 4.13 Impact Factor
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Jiming Li,
Junbo Ge,
Jie Yuan,
Hong Jiang, Hong Ma,
Yanyan Liang,
Yuhong Niu,
Hui Gong,
Ning Zhou,
Aili Guan,
Zhen Ma,
Lingyan Yuan,
Aijun Sun,
Yuqi Wang,
Akira Nakai,
Issei Komuro,
Yunzeng Zou
[show abstract]
[hide abstract]
ABSTRACT: To examine how heat shock transcription factor 1 (HSF1) protects against maladaptive hypertrophy during pressure overload, we subjected HSF1 transgenic (TG), knockout (KO) and wild type (WT) mice to a constriction of transverse aorta (TAC), and found that cardiac hypertrophy, functions and angiogenesis were well preserved in TG mice but were decreased in KO mice compared to WT ones at 4 weeks, which was related to HIF-1 and p53 expression. Inhibition of angiogenesis suppressed cardiac adaptation in TG mice while overexpression of angiogenesis factors improved maladaptive hypertrophy in KO mice. In vitro formation of vasculatures by microvascular endothelial cells was higher in TG mice but lower in KO mice than in WT ones. A siRNA of p53 but not a HIF-1 gene significantly reversed maladaptive hypertrophy in KO mice whereas a siRNA of HIF-1 but not a p53 gene induced maladaptive hypertrophy in TG mice. Heart microRNA analysis showed that miR-378 and miR-379 were differently changed among the three mice after TAC, and miR-378 or siRNA of miR-379 could maintain cardiac adaptation in WT mice. These results indicate that HSF1 preserves cardiac adaptation during pressure overload through p53-HIF-1-associated angiogenesis, which is controlled by miR-378 and miR-379.
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