Netrin-1 Ameliorates Myocardial Infarction-Induced Myocardial Injury: Mechanisms of Action in Rats and Diabetic Mice

Abstract

Netrin-1 is typically known as a neuronal guidance factor. Studies have reported the proangiogenic, antiapoptotic, and antiinflammatory properties of Netrin-1. A critical role for Netrin-1 in ischemic organ damage, myocardial infarction (MI) in particular, has also been demonstrated, making Netrin-1 a potential therapeutic target for the treatment of cardiovascular diseases (CVDs). Mesenchymal stem cells (MSCs) have shown promising therapeutic efficacy in preclinical studies. However, limited clinical success was observed, mainly due to poor MSC survival. Given the reported beneficial impact of Netrin-1 in tissue repair and cell survival, we examined the effects of Netrin-1 in MSC therapy against MI-induced ischemic cardiac injury in rats and type 2 diabetic (T2D) mice. MSCs were isolated and Netrin-1-expressing MSCs were obtained by transduction with a Netrin-1-encoding retroviral vector. The Netrin-1-MSCs were then delivered intramyocardially to the infarct sites of rats and T2D mice with MI. Thirty days after MSC implantation, changes at the infarct area, level of collagen deposition, and cardiac hypertrophy were assessed. Molecular mechanisms underlying the effects of Netrin-1 were also investigated. Attenuated MI-induced myocardial dysfunction was observed after Netrin-1-MSC treatment. Protective effects of the Netrin-1-MSCs were attributable primarily to better MSC survival and migration, which is mediated by Netrin-1-induced phosphorylation of p44/42 mitogen-activated protein kinase. Netrin-1-stimulated nitric oxide production was also responsible, which could promote neovessel formation and progenitor cell mobilization in vivo. We report a protective role for Netrin-1 against MI-induced ischemic injuries, reinstating its promising potential as a therapeutic target for CVDs and, more importantly, for patients with CVD with coexisting diabetes.

Netrin-1 restores cell injury and impaired angiogenesis in vascular endothelial cells upon high glucose by PI3K/AKT-eNOS

“…A previous study also proved an essential role of netrin-1 in angiogenesis of rat placenta (Xie et al 2011). Analogously, netrin-1 expression can improve capillary formation and blood vessel density in mice with diabetic myocardial infarction (Ke et al 2014). Hence, these observations provoke us to conclude that overexpression of netrin-1 may facilitate wound healing of DFU by ameliorating endothelial dysfunction by restoring the impairment of cell growth and vascularization.…”

“…Decreased levels of netrin-1 had been observed in diabetic patients (Liu et al 2016). Importantly, increasing evidences have corroborated the protective role of netrin-1 expression against diabetes-induced complications such as diabetic nephropathy and myocardial infarction (Tak et al 2013, Ke et al 2014. To date, no data are available on its function in diabetes-induced DFU.…”

“…Previous researches have revealed a protective role of netrin-1 against ischemia/ reperfusion kidney injury and cardiac injury (Tak et al 2013, Siu et al 2015. Importantly, ectopic expression of netrin-1 exerts a benefit effect on repair impairment in diabetes-induced myocardial infarction and diabetic nephropathy, making it as a potentially promising agent against diabetic complication (Tak et al 2013, Ke et al 2014. To further elucidate the role of netrin-1 in DFU, we investigated its function in vascular endothelial cell dysfunction under high glucose exposure.…”

“…Emerging report demonstrated the reduction of plasma netrin-1 levels in patients diagnosed with type 2 DM, and netrin-1 levels was found to be negatively related to insulin resistance and glucose homeostasis (Liu et al 2016). Importantly, administration with netrin-1-expressing mesenchymal stem cells facilitated the repair of myocardial infarctiontriggered ischemic injury in diabetic mice by promoting NO production and subsequent neovessel formation (Ke et al 2014). Netrin-1 also exerts the beneficial efficacy in the treatment of diabetic nephropathy (Mohamed et al 2012, Tak et al 2013.…”

“…In umbilical cord blood-derived mesenchymal stem cells (UCB-MSC), netrin-1 protected against hypoxic injury-induced cell apoptosis via the expression of heat shock protein (HSP) 27 (Son et al 2013). The growing body of evidence has corroborated a vital function of netrin-1 in injury repair of multiple diseases (Wang et al 2008, Ke et al 2014. Administration of netrin-1 antagonizes both ischemiareperfusion (I/R) injury of kidney and kidney function repair by suppressing endothelial cell activation and leukocyte infiltration (Wang et al 2008).…”