Preventive Effects of Heregulin-β
            <sub>1</sub>
            on Macrophage Foam Cell Formation and Atherosclerosis

Xu, Gang; Watanabe, Takuya; Iso, Yoshitaka; Koba, Shinji; Sakai, Tetsuo; Nagashima, Masaharu; Arita, Susila; Hongo, Shigeki; Ota, Hidekazu; Kobayashi, Youichi; Miyazaki, Akira; Hirano, Tsutomu

doi:10.1161/circresaha.109.193870

Cited by 61 publications

(78 citation statements)

References 30 publications

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“…(20,33). In this study, we have confirmed that rhNRG-1 suppresses the formation of atherosclerotic lesions in apoEdeficient mice (44).…”

Section: Discussionsupporting

confidence: 77%

“…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). In addition to effects on cardiomyopathy, NRG-1 also has arterioprotective effects by suppressing macrophage foam cell formation (44). These effects have been observed in hypercholesterolemic apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice, and the molecular mechanisms involved reduced endocytosis of acetylated lowdensity lipoprotein and reduced cholesterol ester formation.…”

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confidence: 99%

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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

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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.

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“…(20,33). In this study, we have confirmed that rhNRG-1 suppresses the formation of atherosclerotic lesions in apoEdeficient mice (44).…”

Section: Discussionsupporting

confidence: 77%

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

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“…Previous reports have shown that cardiac GDF15, a member of the transforming growth factor-␤ superfamily, plays an important role in cardioprotection against myocardial ischemia (23) and pathological hypertrophy (52). Since mTORC2 regulates GDF15 expression in the heart (12), we examined GDF15 mRNA expression in the hearts of WT and mTOR-Tg mice fed either NCD or HFD.…”

Section: Effects Of Hfd On Body Weight Gain Glucose Intolerance Andmentioning

confidence: 99%

Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

Aoyagi

Higa

Aoyagi

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring.

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“…caused a signifi cant reduction of cholesterol accumulation in macrophages by downregulating SR-A, LOX-1, and ACAT1 expression and upregulating ABCA1 expression, of which ACAT1 and ABCA1 are considered to be candidate targets for the treatment of atherosclerotic lesions due to their roles in macrophage cholesterol metabolism ( 18,(52)(53)(54)(55). ACAT1 inhibition or downregulation was shown to be atheroprotective in animal models ( 18,(56)(57)(58). ABCA1 acts as the primary gatekeeper for eliminating excess tissue cholesterol and represents the first and rate-controlling step in reverse cholesterol transport ( 59,60 ).…”

Section: Discussionmentioning

confidence: 99%

Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL

Yang

Wang

Yang

et al. 2013

Journal of Lipid Research

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Atherosclerosis contributes chiefl y to ischemic diseases, including coronary heart disease, cerebral infarction, and intermittent claudication. Lipid plaque is the main pathological presentation and is characterized by abundant foam cells, which are derived mostly from macrophages. In the transformation, cholesterol ester accumulation accelerates foam cell formation.Macrophages possess an entrance-to-exit machinery for the modulation of cholesterol metabolism. Scavenger receptor class A (SR-A), CD36, and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) are largely responsible for cholesterol infl ux ( 1-8 ), and ABCA1, ABCG1 and scavenger receptor class B type I (SR-B I) facilitate cholesterol effl ux ( 9-15 ). Free cholesterol inside macrophages is esterifi ed by ACAT1, thereby promoting cholesterol ester accumulation ( 16-18 ). All the molecules form an integrated modulating Abstract Cholesterol-metabolism-associated molecules, including scavenger receptor class A (SR-A), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD36, ACAT1, ABCA1, ABCG1, and scavenger receptor class B type I, can modulate cholesterol metabolism in the transformation from macrophages to foam cells. Voltage-gated potassium channel Kv1.3 has increasingly been demonstrated to play an important role in the modulation of macrophage function. Here, we investigate the role of Kv1.3 in modulating cholesterol-metabolism-associated molecules in human acute monocytic leukemia cell-derived macrophages (THP-1 macrophages) and human monocyte-derived macrophages exposed to oxidized LDL (ox-LDL). Human Kv1.3 and Kv1.5 channels (hKv1.3 and hKv1.5) are expressed in macrophages and form a heteromultimeric channel. The hKv1.3-E314 antibody that we had generated as a specifi c hKv1.3 blocker inhibited outward delayed rectifi er potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specifi c hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol effl ux in THP-1 macrophages and human monocyte-derived macrophages exposed to ox-LDL. The hKv1.3-E314 antibody downregulated SR-A, LOX-1, and ACAT1 expression and upregulated ABCA1 expression in THP-1 macrophages and human monocyte-derived macrophages. Our results reveal that specifi c Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefi ts the treatment of atherosclerotic lesions. Press, October 24, 2012 DOI 10.1194 Specifi c Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL Published, JLR Papers in

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Preventive Effects of Heregulin-β ₁ on Macrophage Foam Cell Formation and Atherosclerosis

Cited by 61 publications

References 30 publications

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

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

Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL

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Preventive Effects of Heregulin-β 1 on Macrophage Foam Cell Formation and Atherosclerosis

Cited by 61 publications

References 30 publications

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

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

Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL

Contact Info

Product

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Preventive Effects of Heregulin-β ₁ on Macrophage Foam Cell Formation and Atherosclerosis