Locally Overexpressing Hepatocyte Growth Factor Prevents Post-ischemic Heart Failure by Inhibition of Apoptosis via Calcineurin-mediated Pathway and Angiogenesis

Guo, Yinghua; He, Jing; Wu, Jun-Lou; Yang, Long; Dai, Sheng; Tan, Xiaoyan; Liang, Lirong

doi:10.1016/j.arcmed.2007.11.001

Cited by 56 publications

(43 citation statements)

References 35 publications

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“…Both others' work and our current study demonstrated the close relationship between age and myocardial apoptosis. Furthermore, recent evidence indicates myocardial apoptosis might be a major cause of post-ischemic heart failure development (Guo et al 2008). Our study not only demonstrated age-induced exacerbation of myocardial apoptosis in animals, but in humans as well.…”

Section: Discussionsupporting

confidence: 53%

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats

Liu

Zhang

Chen

et al. 2011

AGE

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Previous studies indicated aging results in the significant cardiac function decreasing and myocardial apoptosis increasing in normal humans or rats. Additionally, animal experiments demonstrated aging increased myocardial ischemia / reperfusion (MI/R)-induced apoptosis. However, whether more myocardial apoptosis happen in the old acute myocardial infarction (AMI) patients is unclear. Reperfusion injury-induced apoptosis is an important cause of heart failure. This study determined the effect of aging upon myocardial apoptosis and cardiac function in patients suffering AMI. All enrolled AMI patients received percutaneous coronary intervention therapy. Volunteers and AMI patients were assigned to four groups: adult (age <65, n=24) volunteers, elderly (age ≥65, n=21) volunteers, adult (age <65, n=29) AMI patients, and elderly (age ≥65, n=36) AMI patients. Blood samples were obtained from all study participants. Plasma apoptotic markers (soluble form of Fas, tumor necrosis factor alpha, and interleukin 6) levels were determined. Cardiac function was evaluated with echocardiogram and Killip class. Due to lack of a direct apoptotic assay method in live human subjects, an additional animal experiment was performed. Both young (2 months) and old (24 months) rats were subjected to 30-min myocardial ischemia and 3 (for TUNEL/caspase activity apoptotic assay) or 24-h (for cardiac function determination) reperfusion. Compared to adult patients, the elderly patients manifested decreased cardiac function and increased plasma apoptotic marker levels significantly. The animal experiment results (cardiac function and plasma apoptotic markers assays) were consistent with the human result data. Animal TUNEL staining and caspase activity measurement revealed a higher myocardial apoptotic ratio in the older rat group. Aging exacerbated MI/R injury in humans and rats. Differential myocardial apoptosis may play a vital role in mediating the observed effects.

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Section: Discussionsupporting

confidence: 53%

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats

Liu

Zhang

Chen

et al. 2011

AGE

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“…39 Previous studies documented that HGF contributes to cardiac regeneration by affecting tissue resident progenitor cells, inhibiting apoptosis, and improving angiogenesis. 40,41 Moreover, transplanted adipose tissue-derived cells were shown to promote angiogenesis by their secretion of HGF. [42][43][44] Clinical studies additionally demonstrated that elevated HGF levels are associated with improved coronary collateralization in patients with acute coronary syndromes.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Expression Determines Functional Activity of Bone Marrow–Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia

Seeger

Rasper

Koyanagi

et al. 2009

ATVB

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Objective-Bone marrow-derived mononuclear cells (BMCs) improve the functional recovery after ischemia. However, BMCs comprise a heterogeneous mixture of cells, and it is not known which cell types are responsible for the induction of neovascularization after cell therapy. Because cell recruitment is critically dependent on the expression of the SDF-1-receptor CXCR4, we examined whether the expression of CXCR4 may identify a therapeutically active population of BMCs. Methods and Results-Human CXCR4ϩ and CXCR4 Ϫ BMCs were sorted by magnetic beads. CXCR4 ϩ BMCs showed a significantly higher invasion capacity under basal conditions and after SDF-1 stimulation. Hematopoietic or mesenchymal colony-forming capacity did not differ between CXCR4 ϩ and CXCR4 Ϫ BMCs. Injection of CXCR4ϩ BMCs in mice after induction of hindlimb ischemia significantly improved the recovery of perfusion compared to injection of CXCR4 Ϫ BMCs. Likewise, capillary density was significantly increased in CXCR4 ϩ BMC-treated mice. Because part of the beneficial effects of cell therapy were attributed to the release of paracrine effectors, we analyzed BMC supernatants for secreted factors. Importantly, supernatants of CXCR4 ϩ BMCs were enriched in the proangiogenic cytokines HGF and PDGF-BB. Conclusion-CXCR4ϩ BMCs exhibit an increased therapeutic potential for blood flow recovery after acute ischemia. Mechanistically, their higher migratory capacity and their increased release of paracrine factors may contribute to enhanced tissue repair. espite improved interventional and pharmacological therapy, postinfarction heart failure remains a challenge in patients with large myocardial infarctions. 1,2 Cell therapy may provide a novel therapeutic option to modify left ventricular remodeling processes and prevent postinfarction heart failure. Several clinical pilot trials and randomized studies showed beneficial effects of cell therapy on left ventricular ejection fraction. 3 In addition, intracoronary administration of bone marrow-derived mononuclear cells (BMCs) was shown to be associated with a significant reduction of the occurrence of major adverse cardiovascular events after AMI. 4 Most of the clinical studies used BMCs isolated from bone marrow aspirates by density gradient centrifugation for intracoronary cell therapy (for review see 5,6 ). BMCs comprise a heterogeneous mixture of cells containing endothelial progenitor cells (EPCs), hematopoietic progenitor cells, mesenchymal stem cells (MSCs), multipotent adult mesenchymal progenitors, and very small embryonic-like (VSEL) stem cells. Although various studies provide evidence that selected endothelial/hematopoietic progenitor cells expressing the marker CD34 or CD133, 7,8 cultured MSCs, 9 -11 and VSEL cells 12 improve the recovery after acute myocardial infarction, the subsets of cells responsible for these beneficial effects of total BMCs are not yet identified.The chemokine stromal cell-derived factor-1 (SDF-1) and its specific receptor, CXCR4, play a pivotal role in normal cardiovascular develop...

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“…Aside from angiogenic action, it has anti-apoptotic effects via bcl-2 overexpression, can protect from oxidizing damage via neutralization of hydroxyl radicals, and may decrease the size of the fibrotic scar [90]. A number of non-viral studies in the heart have demonstrated decreased scar area, increased capillary density and thus myocardial perfusion [91,92] as well as improved left ventricular function [93], and decreased levels of apoptosis [94]. HGF gene transfer has been demonstrated to be effective in human ischemia, in a clinical study on patients with critical limb ischemia [95].…”

Section: Other Factors and Peptidesmentioning

confidence: 99%

Non‐viral gene therapy for myocardial engineering

Holladay

O’Brien

Pandit

2010

WIREs Nanomed Nanobiotechnol

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Despite significant advances in surgical and pharmacological techniques, myocardial infarction remains the main cause of morbidity in the developed world because no remedy has been found for the regeneration of infarcted myocardium. Once the blood supply to the area in question is interrupted, the inflammatory cascade, among other mechanisms, results in the damaged tissue becoming a scar. The goals of cardiac gene therapy are essentially to minimize damage, to promote regeneration or some combination thereof. While the vector is, in theory, less important than the gene being delivered, the choice of vector can have a significant impact. Viral therapies can have very high transfection efficiencies, but disadvantages include immunogenicity, retroviralmediated insertional mutagenesis and the expense and difficulty of manufacture. For these reasons, researchers have focused on non-viral gene therapy as an alternative. In this review, naked plasmid delivery, or the delivery of complexed plasmids, and cellmediated gene delivery to the myocardium will be reviewed. Pre-clinical and clinical trials in the cardiac tissue will form the core of the discussion. While unmodified stem cells are sometimes considered therapeutic vectors based on paracrine mechanisms of action basic understanding is limited. Thus, only genetically modified cells will be discussed as cell-mediated gene therapy.Ischemic heart disease, which includes acute damage due to myocardial infarction (MI) and chronic damage due to atherosclerotic narrowing of vessels, accounts for 35% of deaths reported in the United States every year [1]. MI, which is literally the death of cardiac tissue due to lack of 2 oxygen supply, is the result of the occlusion of a coronary artery. Within a few hours of interrupted blood supply, affected cardiomyocytes die. While the body has adaptive mechanisms, such as hypertrophy of the undamaged cardiac muscle and the development of collateral blood supply to minimize the damage, ischemic heart disease remains the most common cause of death in developed countries [2].The delivery of plasmid DNA to the myocardium is a complicated problem as the transfection efficiency of unmodified DNA is quite low, but complexation with agents designed to improve transfection can increase the cytotoxicity of the treatment [3]. Delivery of uncomplexed plasmid DNA is conceptually the simplest gene delivery technique, but these plasmids have extremely low transfection efficiencies in vitro and are not particularly effective in vivo. Compared to viral vectors, transgene expression is almost negligible and the expression time is also very limited [4]. However, there are significant advantages in using plasmids instead of viruses, such as ease of preparation (large and small scale), very low immunogenicity (as there are essentially no protein or membrane components in the plasmid), capacity for long term storage, ease of recombinant manipulation and much larger expression cassettes [4]. A variety of non-viral techniques are available to improve...

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Locally Overexpressing Hepatocyte Growth Factor Prevents Post-ischemic Heart Failure by Inhibition of Apoptosis via Calcineurin-mediated Pathway and Angiogenesis

Cited by 56 publications

References 35 publications

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats

CXCR4 Expression Determines Functional Activity of Bone Marrow–Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia

Non‐viral gene therapy for myocardial engineering

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