Endothelium-Derived Neuregulin Protects the Heart Against Ischemic Injury

Abstract

Background Removal of cardiac endothelial cells (EC) has been shown to produce significant detrimental effects on the function of adjacent cardiac myocytes, suggesting that EC play a critical role in autocrine/paracrine regulation of the heart. Despite this important observation, the mediators of the protective function of EC remain obscure. Neuregulin (NRG, a member of the epidermal growth factor family) is produced by EC and cardiac myocytes contain receptors (erbB) for this ligand. We hypothesized that NRG is an essential factor produced by EC, promoting cardioprotection against ischemic injury. Methods and Results We demonstrate that human cardiac EC express and release NRG in response to hypoxia-reoxygenation (H/R). Under conditions where H/R causes significant cardiac myocyte cell death, NRG can significantly decrease apoptosis of isolated adult ventricular myocytes. Co-culturing adult murine myocytes with human umbilical vein, murine lung microvascular, or human coronary artery EC can also protect myocytes against H/R-induced apoptosis. These protective effects are abolished by NRG gene deletion or silencing of NRG expression in EC. Finally, endothelial-selective deletion of NRG in vivo leads to significantly decreased tolerance to ischemic insult, as demonstrated by impaired post-ischemic contractile recovery in a perfused whole organ preparation and larger infarct sizes after coronary artery ligation. Conclusion Together, these data demonstrate that EC-derived NRG plays an important role in cardiac myocyte protection against ischemic injury in the heart and support the idea that manipulation of this signaling pathway may be an important clinical target in this setting.

Expression and secretion of neuregulin-1 in cardiac microvascular endothelial cells treated with angiogenic factors

“…In the heart, NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium (1,2). Hedhli et al have reported that NRG-1 plays an important role in cardiac myocyte protection and angiogenic responses to ischemia injury, and NRG-1 secretion is significantly increased in cardiac endothelial cells in response to hypoxia (14). Our study also showed the expression and secretion of NRG-1 were increased in HCMECs with Hypo/SD stimulation.…”

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…Consistent with this idea, it is known that FGF1 regulates cardiac remodeling by exerting a protective and proliferative effect after MI [18,19]. On the other hand, neuregulins play crucial roles in the adult cardiovascular system by inducing structural organization of sarcomeres, cell integrity, cell-cell adhesion [20], cell survival [21,22] and angiogenesis [23]. In fact, several studies using animal models of heart failure have demonstrated the therapeutic benefits of neuregulins, which improved cardiac performance, attenuated disease markers, and prolonged animal survival [24,25].…”

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

“…Studies have demonstrated that in addition to doxorubicin-induced heart failure, Neuregulin1 also improves cardiac function in ischemiareperfusion, viral infection, and pacing induced heart failure (Liu et al, 2006;Bersell et al, 2009;Hedhli et al, 2011). In addition, Neuregulin1 promotes cell cycle reentry of differentiated adult cardiomyocytes, improves angiogenesis in the heart (Bersell et al, 2009;Hedhli et al, 2011), and promotes embryonic stem cell differentiation into the cardiac lineage (Sun et al, 2011). Clinical trials are ongoing using Neureuglin1 for the treatment of heart failure in patients (Gao et al, 2010).…”

“…Recently, Hedhli and colleagues tested whether endothelial-derived Neuregulin1s are important for protecting the heart from ischemia-reperfusion injury (Hedhli et al, 2011). They generated mice with tamoxifen-inducible and endothelium-selective Neuregulin1 gene knockout by cross-breeding mice with VE-cadherin promoter driven Cre-ER (Monvoisin et al, 2006) and mice carrying homozygously floxed alleles of the Neuregulin1 gene (Yang et al, 2001).…”

“…Heart failure (Liu et al, 1998a) Endothelial specific conditional NRG1 KO Normal cardiac function at baseline. Increased infarct area and apoptosis after ischemia-reperfusion (Hedhli et al, 2011) ErbB2 KO Constitutive ErbB2 KO Homozygous die around E10.5. Defect of ventricular trabeculae (Lee et al, 1995) Cardiomyocyte-specific conditional KO Survived to adulthood.…”