Intravenous Glial Growth Factor 2 (GGF2) Isoform of Neuregulin-1β Improves Left Ventricular Function, Gene and Protein Expression in Rats after Myocardial Infarction

Hill, Michael; Patel, Amish V.; Murphy, A.; Smith, Holly; Galindo, Cristi L.; Pentassuglia, Laura; Peng, Xiao; Lenneman, Carrie Geisberg; Odiete, Oghenerukevwe; Friedman, David; Kronenberg, Marvin W.; Zheng, Siyuen; Zhao, Zhongming; Song, Yanna; Harrell, Frank E.; Srinivas, Maya; Ganguly, Anindita; Iaci, Jennifer F.; Parry, Tom J.; Caggiano, Anthony O.; Sawyer, Douglas B.

doi:10.1371/journal.pone.0055741

Cited by 37 publications

(45 citation statements)

References 29 publications

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“…In support of this concept, cardiac deletion of GLUT4 leads to a lower tolerance to ischemic events associated with a higher rate of ATP depletion (65). Indeed, ischemic insults acutely caused the rapid release of Nrg1␤ from microendothelial cells and phosphorylation of ErbB4 (15,36), and Nrg1␤ ablation in endothelial cells aggravated the harmful consequences of ischemia (38), whereas intravenous injections of the EGFlike domain of Nrg1␤ or GGF2 improved ventricular function in rat and swine models of myocardial infarction (18,27,41). Our present findings suggest that an increase in glucose uptake is one of the protective mechanisms induced by Nrg1␤ in these conditions.…”

Section: E789 Nrg1␤ Promotes Glucose Uptakementioning

confidence: 97%

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Pentassuglia

Heim

Lebboukh

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr861), Akt (Thr308 and Ser473), and its effector AS160 (Thr642). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser473 but does not modify AS160-p-Thr642 or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser473 phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.

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Section: E789 Nrg1␤ Promotes Glucose Uptakementioning

confidence: 97%

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Pentassuglia

Heim

Lebboukh

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…In rats, administration of GGF2 for 4 weeks (commencing 1 week after experimental MI) improved cardiac function and indices of cardiac remodelling, compared with administration of vehicle. 148 These findings were replicated in a large animal model of HF. 149 A phase I study (NCT01258387) 150 to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of single intravenous administrations of GGF2 has been completed, but the results are as yet unpublished.…”

Section: Neuregulin-1mentioning

confidence: 75%

New medical therapies for heart failure

Lueder

Krum

2015

Nat Rev Cardiol

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Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

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“…We have previously demonstrated an increase in the protein expression of the anti-oxidative enzyme, glutathione peroxidase, in non-diabetic post-MI rats treated with NRG-1β [19]. To further explore the anti-oxidative effects of NRG-1β in the setting of diabetic MI, we examined the gene expression of key pro-oxidant enzymes.…”

Section: Resultsmentioning

confidence: 99%

“…In rats or swine with MI-induced myocardial dysfunction, treatment with a second form of rhNRG-1β, glial growth factor 2 (GGF2), improved systolic function and reduced progressive remodeling [13, 19]. Clinical trials with NRG-1β have produced favorable effects on cardiac function of HF patients [14, 20].…”

Section: Introductionmentioning

confidence: 99%

Chronic Neuregulin-1β Treatment Mitigates the Progression of Postmyocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus by Suppressing Myocardial Apoptosis, Fibrosis, and Key Oxidant-Producing Enzymes

Gupte

Lal

Ahmad

et al. 2017

Journal of Cardiac Failure

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Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular morbidity and mortality compared to their non-diabetic counterparts owing to the more frequent development of subsequent heart failure (HF). Neuregulin (NRG)-1β is released from cardiac microvascular endothelial cells and acts as a paracrine factor via the ErbB family of tyrosine kinase receptors expressed in cardiac myocytes to regulate cardiac development and stress responses. Since myocardial NRG-1/ErbB signaling has been documented to be impaired during HF associated with type 1 DM, we examined whether enhancement of NRG-1β signaling via exogenous administration of recombinant NRG-1β could exert beneficial effects against post-MI HF in the type 1 diabetic heart. Type 1 DM was induced in male Sprague Dawley rats by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 ug/kg) twice a week for 7 weeks, starting two weeks prior to experimental MI. Residual left ventricular (LV) function was significantly greater in the NRG-1β-treated STZ-diabetic MI group compared to the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. NRG-1β treatment of STZ-diabetic MI rats was associated with reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant–producing enzymes. These results suggest that recombinant NRG-1β may be a promising therapeutic for HF post-MI in the setting of type 1 DM.

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Intravenous Glial Growth Factor 2 (GGF2) Isoform of Neuregulin-1β Improves Left Ventricular Function, Gene and Protein Expression in Rats after Myocardial Infarction

Cited by 37 publications

References 29 publications

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

New medical therapies for heart failure

Chronic Neuregulin-1β Treatment Mitigates the Progression of Postmyocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus by Suppressing Myocardial Apoptosis, Fibrosis, and Key Oxidant-Producing Enzymes

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