VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

Zhou, Ling; Ma, Wei; Yang, Zhaohui; Zhang, F; Lu, Lichong; Ding, Zhengnian; Ding, Bo; Ha, Tuanzhu; Gao, Xiang; Li, C

doi:10.1038/sj.gt.3302416

Cited by 66 publications

(51 citation statements)

References 23 publications

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“…We have shown in previous publications that overexpression of VEGF and Ang1 improves cardiac function in mouse and rat MI heart models through their angiogenic and antiapoptotic functions (4,15). Here, we have showed that VEGF/Ang1 induced neovascular formation and reduced myocardial apoptosis in infarct and peri-infarct zones of porcine acute MI heart.…”

Section: Discussionmentioning

confidence: 50%

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

Zeng

Chen

Tan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

158

103

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VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.

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Section: Discussionmentioning

confidence: 50%

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

Zeng

Chen

Tan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

158

103

View full text Add to dashboard Cite

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“…This report points out that enhanced level of VEGF may have some role in the inhibition of cardiomyocyte and endothelial cell apoptosis. VEGF could activate the myocardial PI-3K pathway and decrease myocardial infarct size [27]. Basic fibroblast growth factor also plays an important role in cardioprotection against myocardial cell death and arrhythmias in acute myocardial infarction (AMI).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function

Xu¹,

Uemura²,

Dai

et al. 2007

Journal of Molecular and Cellular Cardiology

177

123

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It is hypothesized that the protection of bone marrow stem cells (BMSCs) on ischemic myocardium might be related to the anti-apoptotic effect via paracrine mechanisms. In this study, a wide array of cytokines including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), stromal cell derived factor-1 (SDF-1) and insulin growth factor-1 (IGF-1) were detected in the BMSCs cultured medium by ELISA. Myocyte apoptosis was assayed by DNA fragmentation and annexin-V staining. Myocardial infarction model was produced by ligation of mouse left anterior descending coronary arteries (LAD). Before LAD ligation, mice were myoablated by irradiation and transplanted with bone marrow cells from transgenic green fluorescent protein (GFP) mice. After LAD ligation, animals were administered stem cell factor (SCF, 200 μg / day / kg, i.p.) or saline for 6 days. Animals were sacrificed on end of SCF treatment and four weeks later. Apoptotic cardiomyocytes were assayed after treatment finished by TUNEL. Myocardial function was analyzed by echocardiography and pressure-volume loop. Bcl-2 protein was analyzed by western blotting. Our results showed that cultured BMSCs released VEGF, bFGF, SDF-1 and IGF-1. Hypoxia induced cell apoptosis was diminished in cardiomyocytes co-cultured with BMSCs. Smaller LV dimension and increased LV ejection fraction were seen in SCF treated animals. SCF significantly reduced cardiomyocytes apoptosis within peri-infarct area and up-regulation expression of Bcl-2 in ischemic area. Moreover, conditioned medium from cultured BMSCs also induced up-regulation of Bcl-2 protein in cardiomyocytes. It is concluded that paracrine mediators secreted by BMSCs might be involved in early repair of ischemic heart by preventing cardiomyocytes apoptosis and improving cardiac function.

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“…65 Several strategies to enhance myocardial angiogenesis have been investigated, including delivery of angiogenic genes or growth factors. The candidate angiogenic factors include VEGF-A, [66][67][68][69] 69,82 and porcine 83 models of MI. A combination of fibroblast growth factor-2 and hepatocyte growth factor synergistically stimulated angiogenesis and prevented progression of heart failure in a rat model of MI.…”

Section: Therapeutic Myocardial Angiogenesis As a Potential Therapy Fmentioning

confidence: 99%

Angiogenesis and Cardiac Hypertrophy

Oka

Akazawa

Naito

et al. 2014

Circulation Research

380

178

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Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell-cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myocardial growth and angiogenesis in the pathophysiology of cardiac hypertrophy and heart failure. (Circ Res. 2014;114:565-571.)

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VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

Cited by 66 publications

References 23 publications

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function

Angiogenesis and Cardiac Hypertrophy

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