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

Neuregulin-1 (NRG-1) 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−/−) 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−/− mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE−/− littermates. Vehicle-treated diabetic apoE−/− 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. rhNRG-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.

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TLR9-Deficiency in B Cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

Diabetes ◽

10.2337/db20-0373 ◽

2020 ◽

pp. db200373

Author(s):

Sha Sha ◽

James A Pearson ◽

Jian Peng ◽

Youjia Hu ◽

Juan Huang ◽

...

Keyword(s):

Type 1 Diabetes ◽

B Cells ◽

Mouse Model ◽

Immune Tolerance ◽

Diabetes Mouse

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Lipidomic analysis of meibomian glands from type-1 diabetes mouse model and preliminary studies of potential mechanism

Experimental Eye Research ◽

10.1016/j.exer.2021.108710 ◽

2021 ◽

pp. 108710

Author(s):

Huifeng Wang ◽

Qingjun Zhou ◽

Luqin Wan ◽

Menglong Guo ◽

Chen Chen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mouse Model ◽

Potential Mechanism ◽

Lipidomic Analysis ◽

Meibomian Glands ◽

Diabetes Mouse

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Cardiomyopathy, oxidative stress and impaired contractility in a rheumatoid arthritis mouse model

Heart ◽

10.1136/heartjnl-2018-312979 ◽

2018 ◽

Vol 104 (24) ◽

pp. 2026-2034 ◽

Cited By ~ 10

Author(s):

Gianluigi Pironti ◽

Alex Bersellini-Farinotti ◽

Nilesh M Agalave ◽

Katalin Sandor ◽

Teresa Fernandez-Zafra ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Heart Failure ◽

Mouse Model ◽

Posttranslational Modifications ◽

Contractile Function ◽

Joint Inflammation ◽

Left Ventricular ◽

Increased Risk ◽

Fractional Shortening

ObjectivesPatients with rheumatoid arthritis (RA) display an increased risk of heart failure independent of traditional cardiovascular risk factors. To elucidate myocardial disease in RA, we have investigated molecular and cellular remodelling of the heart in an established mouse model of RA.MethodsThe collagen antibody-induced arthritis (CAIA) RA mouse model is characterised by joint inflammation and increased inflammatory markers in the serum. We used CAIA mice in the postinflammatory phase that resembles medically controlled RA or RA in remission. Hearts were collected for cardiomyocyte isolation, biochemistry and histology analysis.ResultsHearts from mice subjected to CAIA displayed hypertrophy (heart/body weight, mean±SD: 5.9±0.8vs 5.1±0.7 mg/g, p<0.05), fibrosis and reduced left ventricular fractional shortening compared with control. Cardiomyocytes from CAIA mice showed reduced cytosolic [Ca2+]i transient amplitudes (F/F0, mean±SD: 3.0±1.2vs 3.6±1.5, p<0.05) that was linked to reductions in sarcoplasmic reticulum (SR) Ca2+ store (F/F0, mean±SD: 3.5±1.3vs 4.4±1.3, p<0.01) measured with Ca2+ imaging. This was associated to lower fractional shortening in the cardiomyocytes from the CAIA mice (%FS, mean±SD: 3.4±2.2 vs 4.6%±2.3%, p<0.05). Ca2+ handling proteins displayed oxidation-dependent posttranslational modifications that together with an increase in superoxide dismutase expression indicate a cell environment with oxidative stress.ConclusionsThis study shows that inflammation during active RA has long-term consequences on molecular remodelling and contractile function of the heart, which further supports that rheumatology patients should be followed for development of heart failure.

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Abstract 352: Myocardial Neuregulin-1/ErbB Signaling Is Impaired in the Setting of Post--Myocardial Infarction Heart Failure Complicated by Type 1 Diabetes Mellitus

Circulation Research ◽

10.1161/res.111.suppl_1.a352 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Oghenerukevwe Odiete ◽

Kathleen E Dennis ◽

Douglas B Sawyer ◽

Michael F Hill

Keyword(s):

Diabetes Mellitus ◽

Myocardial Infarction ◽

Heart Failure ◽

Type 1 Diabetes ◽

Protein Expression ◽

Type 1 Diabetes Mellitus ◽

Neuregulin 1 ◽

Erbb Signaling ◽

Type 1 Dm

Background: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) are at heightened risk for the subsequent development of heart failure (HF). Despite the worse outcomes, investigations into the pathophysiological mechanisms that contribute to the increased frequency of HF after MI in the type 1 DM heart remain scarce. Neuregulin-1 (NRG-1), along with the ErbB family of receptor tyrosine kinases through which NRG-1 ligands signal, have been shown to be intimately involved in mediating cardiac recovery after MI. However, the impact of type 1 DM on this signaling system post-MI remains to be elucidated. Therefore, in the present study, we examined myocardial NRG-1/ErbB signaling during post-MI HF in the presence of type 1 DM. Methods: Type 1 DM was induced in male Sprague-Dawley rats via a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left anterior descending (LAD) coronary artery. Residual left ventricular (LV) function was assessed by echocardiography at 4 weeks post-MI. Following echocardiographic assessment, NRG-1, ErbB2, and ErbB4 protein expression was assessed in the remote, surviving LV myocardium of DM and non-DM rats using Western blot techniques. Results: LV Fractional Shortening (FS) and LV Ejection Fraction (EF) were significantly lower in the DM + MI group compared to the MI group ([LVFS: DM + MI, 17.9 ± 0.7 (n=6) vs. MI, 25.2 ± 2.2 (n=6), p <0.05; LVEF: DM + MI, 35.5 ± 1.4 (n=6) vs. MI, 47.5 ± 3.5 (n=6), p <0.05]), indicating an increased functional severity of HF in the diabetic post-MI group. The weight of myocardial scar caused by the infarction was not significantly different between the MI groups ([DM + MI, 0.19 ± 0.02 g (n=4) vs. MI, 0.20 ± 0.03 g (n=4), p =0.70]). ErbB2, ErbB4, and NRG-1 protein expression levels were all significantly lower in the DM + MI group compared to the MI group. Conclusions: These findings demonstrate that type 1 DM impairs myocardial NRG-1/ErbB signaling in response to MI, which may contribute to the accelerated progression of subsequent HF. Augmentation of NRG-1 or its downstream signaling pathways may represent a novel therapeutic strategy for ameliorating post-MI HF in the setting of type 1 DM.

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Akt/hypoxia-inducible factor-1α signaling deficiency compromises skin wound healing in a type 1 diabetes mouse model

Experimental and Therapeutic Medicine ◽

10.3892/etm.2015.2394 ◽

2015 ◽

Vol 9 (6) ◽

pp. 2141-2146 ◽

Cited By ~ 5

Author(s):

LIFENG JING ◽

SHUANG LI ◽

QIN LI

Keyword(s):

Wound Healing ◽

Type 1 Diabetes ◽

Mouse Model ◽

Hypoxia Inducible Factor ◽

Skin Wound ◽

Skin Wound Healing ◽

Hypoxia Inducible Factor 1Α ◽

Diabetes Mouse

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Cardiac Tissue Factor Regulates Inflammation, Hypertrophy and Heart Failure in Mouse Model of Type 1 Diabetes

Diabetes ◽

10.2337/db20-0719 ◽

2021 ◽

pp. db200719

Author(s):

Mary Cibi Dasan ◽

Reddemma Sandireddy ◽

Hanumakumar Bogireddy ◽

Nicole Tee ◽

Siti Aishah Binte Abdul Ghani ◽

...

Keyword(s):

Heart Failure ◽

Type 1 Diabetes ◽

Mouse Model ◽

Tissue Factor ◽

Cardiac Tissue

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Macrophages from a type 1 diabetes mouse model present dysregulated Pl3K/AKT, ERK 1/2 and SAPK/JNK levels

Immunobiology ◽

10.1016/j.imbio.2019.11.014 ◽

2020 ◽

Vol 225 (2) ◽

pp. 151879 ◽

Cited By ~ 2

Author(s):

Fernando Henrique Galvão Tessaro ◽

Thais Soprani Ayala ◽

Leonardo Mendes Bella ◽

Joilson Oliveira Martins

Keyword(s):

Type 1 Diabetes ◽

Mouse Model ◽

Diabetes Mouse

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Abstract 249: Chronic Neuregulin-1β Treatment Mitigates the Progression of Post-myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

Circulation Research ◽

10.1161/res.121.suppl_1.249 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Manisha Gupte ◽

Hind Lal ◽

Firdos Ahmad ◽

Lin Zhong ◽

Douglas B Sawyer ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Type 1 Diabetes ◽

Heart Function ◽

Diabetic Rats ◽

Left Ventricular ◽

Lv Function ◽

Coronary Artery Ligation ◽

Artery Ligation

Aim: Neuregulin-1β (NRG-1β), a growth factor critical for cardiac development as well as maintenance of heart function after injury has been shown to significantly improve heart function in preclinical rodent models. Importantly, number of studies are ongoing to test the efficacy of NRG-1β as a treatment for patients with chronic heart failure. However, the efficacy of recombinant NRG-1β in a typ1 diabetic model of heart failure due to myocardial infarction (MI) has not been investigated. The aim of the present study was to determine the efficacy of exogenous NRG-1β to improve residual cardiac function after MI in type1 diabetic rats. Methods and Results: Sprague Dawley rats were induced type 1 diabetes by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 diabetes, 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. Furthermore, NRG-1β treatment in STZ-diabetic MI rats reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes. Conclusion: This study demonstrates that augmentation of NRG-1β signaling in STZ-diabetic post-MI rats via therapy with exogenous recombinant NRG-1β will alleviate subsequent HF through improvements in residual LV function via protection against adverse remodeling and apoptosis.

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