Abstract
Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (Met) play important roles in myocardial function both in physiological and pathological situations. In the developing heart, HGF influences cardiomyocyte proliferation and differentiation. In the adult, HGF/Met signaling controls heart homeostasis and prevents oxidative stress in normal cardiomyocytes. Thus, the possible cardiotoxicity of current Met-targeted anti-cancer therapies has to be taken in consideration. In the injured heart, HGF plays important roles in cardioprotection by promoting: (1) prosurvival (anti-apoptotic and anti-autophagic) effects in cardiomyocytes, (2) angiogenesis, (3) inhibition of fibrosis, (4) anti-inflammatory and immunomodulatory signals, and (5) regeneration through activation of cardiac stem cells. Furthermore, we discuss the putative role of elevated HGF as prognostic marker of severity in patients with cardiac diseases. Finally, we examine the potential of HGF-based molecules as new therapeutic tools for the treatment of cardiac diseases.
Highlights
Hepatocyte growth factor (HGF) is a pleiotropic cytokine controlling different cellular processes, such as migration, morphogenesis, apoptosis and proliferation
Further studies performed through conditional, lineage specific Met knockout models will be useful to better determine the physiological roles of HGF/Met axis in the various cell populations which constitute the heart tissues, such as cardiac fibroblasts, endothelial cells, cardiac progenitor cells (CPCs), etc
These studies might reveal a more complex picture of HGF/Met involvement in the physiological regulation of cardiac functions and will provide a rational basis to follow the potential cardiotoxicity of Met-targeted anti-tumor therapies in selected cancer patients
Summary
Hepatocyte growth factor (HGF) is a pleiotropic cytokine controlling different cellular processes, such as migration, morphogenesis, apoptosis and proliferation. We initially describe its essential role in the maintenance of normal adult myocardial function In this context, we provide our perspective on the cardiac implications of anti-cancer therapies that neutralize Met activity. Given the critical role played by HGF/Met couple in myocardial protection (see above and below), consideration must be given to the possible cardiac side effects of Met-targeted cancer therapy. Met inhibitors, such as Crizotinib or PF-04254644, have been tested by short-term treatments of cellular and pre-clinical models and have been shown to induce cardiomyocytes death through molecular mechanisms involving ROS production, activation of caspases, alteration of cell metabolism and blockage of ion channels [13,14]. A great deal of evidence has shown the importance of HGF/Met system in cardiac repair after MI (for a review see [19])
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