title: Cellular and molecular mechanisms of HGF/Met in the cardiovascular system.
abstract: Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Gallo
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sala
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gatti
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy tiziana.crepaldi@unito.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Crepaldi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: Angiogenesis; Autophagy; Cardiovascular system; HGF/Met; SXS; Signalling; TGF-β/BMP7/Smad pathway fibrosis; angiogenesis; cardioprotection; fibrosis; immunomodulation; regeneration; signalling; signalling pathway