Retinol-Binding Protein 4 Induces Cardiomyocyte Hypertrophy by Activating TLR4/MyD88 Pathway.
Insulin resistance plays a major role in the development and progression of cardiac hypertrophy and heart failure. Heart failure in turn promotes insulin resistance and increases the risk for diabetes. The vicious cycle determines significant mortality in patients with heart failure and diabetes. However, the underlying mechanisms for the vicious cycle are not fully elucidated. Here we show that circulating levels and adipose expression of retinol-binding protein 4 (RBP4), an adipokine that contributes to systemic insulin resistance, were elevated in cardiac hypertrophy induced by transverse aortic constriction and angiotensin-II (Ang-II) infusion. Ang-II increased RBP4 expression in adipocytes, which was abolished by losartan, an Ang-II receptor blocker. The elevated RBP4 in cardiac hypertrophy may have pathophysiological consequences because RBP4 increased cell size, enhanced protein synthesis, and elevated the expression of hypertrophic markers including Anp, Bnp, and Myh7 in primary cardiomyocytes. Mechanistically, RBP4 induced the expression and activity of toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) in cardiomyocytes, resulting in enhanced inflammation and reactive oxygen species production. Inhibition or knockdown of the TLR4/MyD88 pathway attenuated inflammatory and hypertrophic responses to RBP4 stimulation. Importantly, RBP4 also reduced the expression of glucose transporter-4 and impaired insulin-stimulated glucose uptake in cardiomyocytes. This impairment was ameliorated in cardiomyocytes from TLR4 knockout mice. Therefore, RBP4 may be a critical modulator promoting the vicious cycle of insulin resistance and heart failure by activating TLR4/MyD88-mediated inflammatory pathways. Potentially, lowering RBP4 might break the vicious cycle and improve both insulin resistance and cardiac hypertrophy.
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Wei
W
Gao
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Hao
H
Wang
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Lin
L
Zhang
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Yang
Y
Cao
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Ji-Zhang
JZ
Bao
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Zheng-Xia
ZX
Liu
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Lian-Sheng
LS
Wang
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Qin
Q
Yang
Department of Geriatrics (W.G., Z.-X.L., X.L.), the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Department of Medicine, Physiology, and Biophysics (W.G., L.Z., Y.C., J.-Z.B., Q.Y.), Center for Diabetes Research and Treatment, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, California 92697; and Department of Cardiology (H.W., L.-S.W.), the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Xiang
X
Lu
D017667:Adipocytes / Q000378:metabolism; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D007249:Inflammation / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C502487:Rbp4 protein, mouse; D017382:Reactive Oxygen Species; D054839:Retinol-Binding Proteins, Plasma; D051197:Toll-Like Receptor 4; D000804:Angiotensin II; D019808:Losartan