Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1β/ErbB in response to myocardial infarction resulting in worsening heart failure

Odiete, Oghenerukevwe; Konik, Ewa; Sawyer, Douglas B.; Hill, Michael

doi:10.1186/1475-2840-12-52

Cited by 22 publications

(25 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NRG-1/ErbB system is necessary for physiological adaptation of the heart to the changes of cardiac demand, and disruption of this system impairs recovery of cardiac contractile function [15]. Odiete et al reported diabetes can prevent compensatory up-regulation of myocardial NRG-1/ErbB after myocardial infarction coincident with an increased severity of heart failure [16]. Previous studies also reported NRG-1 can improve cardiac function in animal models of heart disease including ischemic, dilated, and viral cardiomyopathy [17, 18].…”

Section: Discussionmentioning

confidence: 99%

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Gui

Zeng

Chen³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. Methods: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days. Cardiac function was assessed using catheter MPA cardiac function analysis system. Myocardial blood flow (MBF) was assessed with stable-isotope labeled microspheres. Capillary density was measured by CD31 immunohistochemistry. The protein expression and receptors phosphorylation were assessed using western blot. Results: Left ventricular function, capillary density and MBF were significantly reduced in DCM group when compared with those in the control group (P< 0.01, P< 0.01 and P< 0.05 respectively). Left ventricular function and capillary density were significantly increased in NRG-1 treatment group when compared with those in the DCM group (P< 0.05 and P< 0.05 respectively). The expression of VEGF and Ang-1 and the phosphorylation of Flk1 and Tie-1 were significantly decreased in DCM group as compared with those in the control group. However, those in the NRG-1 treatment group were significantly increased as compared with those in the DCM group. In vitro, NRG-1 treatment increased significantly the expression of VEGF and Ang-1 in human coronary artery smooth muscle cells. Conclusions: NRG-1 can increase the myocardial angiogenesis of DCM, probably via the direct effects of NRG-1 and via the increasing expression of VEGF and Ang-1. These findings may contribute to developing a novel approach to reverse the impaired angiogenic responses in diabetes or coronary artery disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Gui

Zeng

Chen³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Based on our findings and relevant literature, one could assume that CSC function would be further impaired, but this important point deserves further study. 30,31 Most importantly, current CSC culture standard operating procedures in clinical testing invariably subject cells to 25 mmol/L glucose culture conditions because this represents the industry standard for mammalian cell culture. The origin of this nonphysiological glucose content is based on the use of commercially sourced basal media formulations (Iscove's Modified Dulbecco's Medium), which early reports found enhanced hematopoietic cell proliferation.…”

Section: Molgat Et Al Effect Of Hyperglycemia On Cardiac Stem Cells S75mentioning

confidence: 99%

Hyperglycemia Inhibits Cardiac Stem Cell–Mediated Cardiac Repair and Angiogenic Capacity

et al. 2014

View full text Add to dashboard Cite

Background-The impact of diabetes mellitus on the cardiac regenerative potential of cardiac stem cells (CSCs) is unknown yet critical, given that individuals with diabetes mellitus may well require CSC therapy in the future. Using human and murine CSCs from diabetic cardiac tissue, we tested the hypothesis that hyperglycemic conditions impair CSC function. Methods and Results-CSCs cultured from the cardiac biopsies of patients with diabetes mellitus (hemoglobin A1c, 10±2%) demonstrated reduced overall cell numbers compared with nondiabetic sourced biopsies (P=0.04). When injected into the infarct border zone of immunodeficient mice 1 week after myocardial infarction, CSCs from patients with diabetes mellitus demonstrated reduced cardiac repair compared with nondiabetic patients. Conditioned medium from CSCs of patients with diabetes mellitus displayed a reduced ability to promote in vitro blood vessel formation (P=0.02). Similarly, conditioned medium from CSCs cultured from the cardiac biopsies of streptozotocin-induced diabetic mice displayed impaired angiogenic capacity (P=0.0008). Somatic gene transfer of the methylglyoxal detoxification enzyme, glyoxalase-1, restored the angiogenic capacity of diabetic CSCs (diabetic transgenic versus nondiabetic transgenic; P=0.8). Culture of nondiabetic murine cardiac biopsies under high (25 mmol/L) glucose conditions reduced CSC yield (P=0.003), impaired angiogenic (P=0.02) and chemotactic (P=0.003) response, and reduced CSC-mediated cardiac repair (P<0.05). Conclusions-Diabetes mellitus reduces the ability of CSCs to repair injured myocardium. Both diabetes mellitus andpreconditioning CSCs in high glucose attenuated the proangiogenic capacity of CSCs. In this study, we have investigated the effects of diabetes mellitus and a hyperglycemic environment on the function of ex vivo proliferated human and murine CSCs. Furthermore, we assessed the ability of GLO-1 overexpression to prevent and reverse hyperglycemia-induced CSC dysfunction. MethodsDetailed experimental methods are available in the online-only Data Supplement. CSC Isolation and CultureHuman CSCs were obtained from left atrial appendages donated by patients (aged 18-80 years) undergoing clinically indicated heart surgery after informed consent. Murine CSCs were obtained from cardiac tissue of wild-type C57Bl/6, C57Bl/6-cKit-EGFP, or C57Bl/6-PEP8-hGlo-1 transgenic mice (aged 2 to 12 months) under isoflurane sedation. CSCs were cultured as described previously. 19,20 Hyperglycemia was induced in C57BL/6 or PEP8-hGlo-1 mice by intraperitoneal injection of streptozotocin (50 mg/kg for 5 days) in 0.05 mol/L sodium citrate. Nondiabetic control mice received equal volumes of 0.05 mol/L sodium citrate. Fasting blood glucose measurements were obtained 10 to 14 days after the fifth streptozotocin injection and again before euthanasia. Mean fasting blood glucose at the time of euthanasia was 29.0±2.3 mmol/L for streptozotocin-injected animals versus 5.6±0.1 mmol/L for controls (P=0.0005). Diabetic Cardiac Explant GLO-1 and...

show abstract

“…In animals, recombinant NRG-1 has beneficial effects on several forms of cardiomyopathy, including ischemic, toxic, viral, and diabetic cardiomyopathy (23,26). With specific relation to diabetes, endogenous NRG-1 signaling may be impaired in type 1 diabetic cardiomyopathy, while exogenous treatment with NRG-1 has reversed cardiac remodeling in diabetic rats (14,22,23,34). Currently, two forms of recombinant NRG-1 are being examined in clinical trials as potential therapies for heart failure with a reduced left ventricular (LV) ejection fraction (12,17).…”

mentioning

confidence: 99%

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Vandekerckhove

Vermeulen

Liu

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Vandekerckhove L, Vermeulen Z, Liu ZZ, Boimvaser S, Patzak A, Segers VF, De Keulenaer GW. Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk. Am J Physiol Endocrinol Metab 310: E495-E504, 2016. First published January 19, 2016 doi:10.1152/ajpendo.00432.2015 is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE Ϫ/Ϫ ) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE Ϫ/Ϫ mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE Ϫ/Ϫ littermates. Vehicle-treated diabetic apoE Ϫ/Ϫ mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rh-NRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys.

show abstract

Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1β/ErbB in response to myocardial infarction resulting in worsening heart failure

Cited by 22 publications

References 43 publications

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Hyperglycemia Inhibits Cardiac Stem Cell–Mediated Cardiac Repair and Angiogenic Capacity

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Contact Info

Product

Resources

About