Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease (a major cause of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

(MI)), as well as treatment for the damage that occurs to the heart after MI. After MI, the myocardium suffers from

reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...

which leads to death of cardiomyocytes and detrimental remodelling of the heart, consequently reducing proper cardiac function.

Transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to des ...

of cardiac myocytes with human HGF reduces

ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...

reperfusion injury after MI. The benefits of HGF therapy include preventing improper remodelling of the heart and ameliorating heart dysfunction post-MI.

Human hepatocyte growth factor

Human hepatocyte growth factor (HGF) is an 80kD pleiotropic protein that is endogenously produced by a variety of cell types from the

mesenchymal Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every ...

cell lineage (such as

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

and neurons). It is produced and proteolytically cleaved to its active state in response to cellular injury or during apoptosis. HGF binds to c-met receptors found on mesenchymal cell types to produce its many different effects such as increased cellular motility, morphogenesis, proliferation and differentiation. Research has shown that HGF has potent

angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...

, anti-fibrotic, and anti-apoptotic properties. It has also been shown to act as a chemoattractant for adult mesenchymal stem cells via c-met receptor binding.

Research and clinical trials

Animal research has demonstrated that administration of HGF cDNA plasmids into ischemic cardiac tissue can increase cardiac function (improved left ventricular ejection fraction and fractional shortening compared to control subjects) after induced MI or ischemia. Transfection with HGF plasmids in damaged cardiac tissue also promotes angiogenesis (increased capillary density compared to control subjects), as well as decreasing detrimental remodelling of the tissue at the site of injury (decreased fibrotic deposition). The increased production of HGF by transfected cardiomyocytes during injury has also shown to be a powerful chemo-attractant of adult mesenchymal stem cells via HGF/c-Met binding. The

mitogenic A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...

and morphogenic properties of HGF induce recruited stem cells to take on cardiomyocyte phenotypes, potentially helping in the healing of ischemic tissue. The benefits of HGF in experimental models have led to its investigation in clinical trials. A

phase I clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

entailed injecting an adenovirus

vector Vector most often refers to: *Euclidean vector, a quantity with a magnitude and a direction *Vector (epidemiology), an agent that carries and transmits an infectious pathogen into another living organism Vector may also refer to: Mathematic ...

with the human HGF (Ad-hHGF) gene into the coronary vessels localized to ischemic tissue. Results demonstrate that it is in fact safe to administer the Ad-hHGF vector into patients with coronary artery disease in hopes of re-vascularizing damaged tissue in patients for which coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) are not available or possible. Despite the trial’s limitations (''i.e.'' no assessment of left ventricular function and sample size was quite small), upon follow up assessments at 12 months, none of the patients receiving the treatment had been readmitted to hospital for MI, angina or aggravated heart failure.

References

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