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.

Hepatocyte growth factor demonstrates racial heterogeneity as a biomarker for coronary heart disease

“…18 A substantial body of evidence exists regarding the cardioprotective effects of these tissue activities in atherosclerotic heart disease, which have been summarised previously. 2 In contrast, the angiogenic properties of HGF and associations of circulating HGF and cardiovascular risk factors and disease implicate HGF in atherosclerotic disease. Despite the uncertainty regarding the role of HGF in atherosclerosis, HGF has been hypothesised as a potential biomarker for disease prediction as well as a biomarker of disease burden.…”

“…1 Evidence is mounting that indicates HGF activities have cardioprotective effects in tissues through activation of antiapoptotic, anti-inflammatory, antioxidant and antifibrotic pathways. 2 However, it is unknown if HGF contributes to the progression of atherosclerosis given that it is also a strong promoter of angiogenesis, 3 4 an essential component of atherosclerotic plaque neovascularisation. Subsequent research has shown that circulating HGF is elevated as a compensatory response to endothelial damage and accumulates in injured organs via its receptor c-MET.…”

Hepatocyte Growth Factor Is Positively Associated With Risk of Stroke

“…Their favorable effects in the heart and vasculature include anti-inflammatory, anti-fibrotic, and pro-angiogenic actions. 1 Because HGF is released in response to endothelial injury, higher levels of circulating HGF are associated with hypertension, diabetes, smoking, increased age, body mass index (BMI), and presence and severity of atherosclerotic disease in both the heart and lower extremities. 1–12 …”

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…All this evidence suggests that autophagy per se contributes to some extent to the regenerative potential of the human heart. [101]. This group previously showed that Met-agonist antibodies and HGF administration induced an mTOR-dependent anti-autophagic effect, which promoted cardiomyocyte survival under cobalt-chloride induced hypoxic/ischemic conditions [102].…”