Endogenous Bioactive Peptides as Potential Biomarkers for Atherosclerotic Coronary Heart Disease

Cardiovascular disease is the leading cause of death worldwide, with high medical costs and rates of disability. It is therefore important to evaluate the use of cardiovascular biomarkers in the early diagnosis of coronary artery disease (CAD). We have screened a variety of recently identified bioactive peptides candidates in anticipation that they would allow detection of atherosclerotic CAD. Especially, we have focused on novel anti-atherogenic peptides as indicators and negative risk factors for CAD. In vitro, in vivo and clinical studies indicated that human adiponectin, heregulin-β1, glucagon-like peptide-1 (GLP-1), and salusin-α, peptides of 244, 71, 30, and 28 amino acids, respectively, attenuate the development and progression of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-coenzyme A: cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are significantly decreased in patients with CAD compared to patients without CAD. Receiver operating characteristic analyses showed that salusin-α is a more useful biomarker, with better sensitivity and specificity, compared with the others for detecting CAD. Therefore, salusin-α, heregulin-β1, adiponectin, and/or GLP-1, alone or in various combinations, may be useful as biomarkers for atherosclerotic CAD.

[1]  D. Sawyer,et al.  Circulating neuregulin-1&bgr; levels vary according to the angiographic severity of coronary artery disease and ischemia , 2011, Coronary artery disease.

[2]  A. Miyazaki,et al.  Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. , 2009, Current medicinal chemistry.

[3]  K. Walsh,et al.  Adiponectin as an anti-inflammatory factor. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[4]  Lu Yan,et al.  Salusins Protect Neonatal Rat Cardiomyocytes from Serum Deprivation-induced Cell Death Through Upregulation of GRP78 , 2006, Journal of cardiovascular pharmacology.

[5]  M. Shichiri,et al.  The roles of salusins in atherosclerosis and related cardiovascular diseases. , 2011, Journal of the American Society of Hypertension : JASH.

[6]  D. Drucker The biology of incretin hormones. , 2006, Cell metabolism.

[7]  Yu Jin,et al.  Adiponectin Induces Vascular Smooth Muscle Cell Differentiation via Repression of Mammalian Target of Rapamycin Complex 1 and FoxO4 , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[8]  T. Suter,et al.  Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. , 2006, Journal of molecular and cellular cardiology.

[9]  T. Funahashi,et al.  Future adverse cardiac events can be predicted by persistently low plasma adiponectin concentrations in men and marked reductions of adiponectin in women after acute myocardial infarction. , 2007, Atherosclerosis.

[10]  M. Shichiri,et al.  Chronic infusion of salusin-alpha and -beta exerts opposite effects on atherosclerotic lesion development in apolipoprotein E-deficient mice. , 2010, Atherosclerosis.

[11]  V. Boyko,et al.  Usefulness of combining serum uric acid and C-reactive protein for risk stratification of patients with coronary artery disease (Bezafibrate Infarction Prevention [BIP] study). , 2009, The American journal of cardiology.

[12]  Stephen E Kimmel,et al.  Neuregulin-1β Is Associated With Disease Severity and Adverse Outcomes in Chronic Heart Failure , 2009, Circulation.

[13]  Y. Matsuzawa Adiponectin: a key player in obesity related disorders. , 2010, Current pharmaceutical design.

[14]  Y. Izumiya,et al.  A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. , 2012, Journal of the American College of Cardiology.

[15]  A. El-Menyar,et al.  Total and high molecular weight adiponectin in patients with coronary artery disease , 2009, Journal of cardiovascular medicine.

[16]  Y. Iso,et al.  Pathogenic involvement of heregulin-β1 in anti-atherogenesis , 2012, Regulatory Peptides.

[17]  R. Levi,et al.  Neuregulin-1beta1 rapidly modulates nitric oxide synthesis and calcium handling in rat cardiomyocytes. , 2010, Cardiovascular research.

[18]  M. Bajaj,et al.  Adiponectin and vulnerable atherosclerotic plaques. , 2011, Journal of the American College of Cardiology.

[19]  Lei Gong,et al.  Glucagon-like peptide 1 protects microvascular endothelial cells by inactivating the PARP-1/iNOS/NO pathway , 2011, Molecular and Cellular Endocrinology.

[20]  M. Shichiri,et al.  Serum levels and urinary excretion of salusin-α in renal insufficiency , 2010, Regulatory Peptides.

[21]  T. Tateno,et al.  Presence of immunoreactive salusin-α in human serum and urine , 2006, Peptides.

[22]  S. Tsimikas Oxidative biomarkers in the diagnosis and prognosis of cardiovascular disease. , 2006, The American journal of cardiology.

[23]  E. Zakynthinos,et al.  Inflammatory biomarkers in coronary artery disease. , 2009, Journal of cardiology.

[24]  MasayoshiShichiri,et al.  Impact of Salusin-α and -β on Human Macrophage Foam Cell Formation and Coronary Atherosclerosis , 2008 .

[25]  L. Ding,et al.  Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells , 2011, Acta Pharmacologica Sinica.

[26]  H. Motoshima,et al.  Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL. , 2004, Biochemical and biophysical research communications.

[27]  W. Garvey,et al.  Macrophage Adiponectin Expression Improves Insulin Sensitivity and Protects Against Inflammation and Atherosclerosis , 2010, Diabetes.

[28]  S. Kihara,et al.  Adiponectin Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice , 2002, Circulation.

[29]  M. Shichiri,et al.  Serum Salusin-α Levels Are Decreased and Correlated Negatively with Carotid Atherosclerosis in Essential Hypertensive Patients , 2008, Hypertension Research.

[30]  P. Lepper,et al.  High-molecular weight adiponectin is independently associated with the extent of coronary artery disease in men. , 2008, Atherosclerosis.

[31]  P. Macdonald,et al.  Parenteral administration of recombinant human neuregulin‐1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses , 2011, European journal of heart failure.

[32]  B. Ford,et al.  Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression , 2005, Neurobiology of Disease.

[33]  R. Shannon,et al.  Glucagon-Like Peptide-1 Limits Myocardial Stunning following Brief Coronary Occlusion and Reperfusion in Conscious Canines , 2005, Journal of Pharmacology and Experimental Therapeutics.

[34]  B. Ford,et al.  Neuregulin-1 Attenuates Neointimal Formation following Vascular Injury and Inhibits the Proliferation of Vascular Smooth Muscle Cells , 2007, Journal of Vascular Research.

[35]  S. Kihara,et al.  Adiponectin down-regulates acyl-coenzyme A:cholesterol acyltransferase-1 in cultured human monocyte-derived macrophages. , 2004, Biochemical and biophysical research communications.

[36]  A. Roy,et al.  Role of biomarkers in risk stratification of acute coronary syndrome , 2010, The Indian journal of medical research.

[37]  J. Holst,et al.  Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease , 2010, Diabetologia.

[38]  S. Kihara,et al.  Adipocyte-Derived Plasma Protein Adiponectin Acts as a Platelet-Derived Growth Factor-BB–Binding Protein and Regulates Growth Factor–Induced Common Postreceptor Signal in Vascular Smooth Muscle Cell , 2002, Circulation.

[39]  E. Ingelsson,et al.  Plasma levels of glucagon like peptide‐1 associate with diastolic function in elderly men , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[40]  Liuquan Cheng,et al.  A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. , 2010, Journal of the American College of Cardiology.

[41]  B. Staels,et al.  Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR. , 2004, Biochemical and biophysical research communications.

[42]  M. Shichiri Reply to 'Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities' , 2007, Nature Medicine.

[43]  S. Kihara,et al.  Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages , 2001, Circulation.

[44]  S. Koba,et al.  Roles of Serotonin in Atherothrombosis and Related Diseases , 2012 .

[45]  A. Işık,et al.  Serum salusin-alpha level in rheumatoid arthritis , 2011, Regulatory Peptides.

[46]  F. Wang,et al.  Associations of serum salusin-alpha levels with atherosclerosis and left ventricular diastolic dysfunction in essential hypertension , 2012, Journal of Human Hypertension.

[47]  S. Kihara,et al.  Adiponectin protects against the development of systolic dysfunction following myocardial infarction. , 2007, Journal of molecular and cellular cardiology.

[48]  R. Kawamori,et al.  Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4 , 2010, Diabetes.

[49]  Masatsugu Hori,et al.  Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  D. Carling,et al.  Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells , 2007, Diabetes.

[51]  Y. Nakano,et al.  A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin Published, JLR Papers in Press, April 7, 2006. , 2006, Journal of Lipid Research.

[52]  山本 和美,et al.  Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages , 2011 .

[53]  Yu-Cheng Hsieh,et al.  Decreased circulating protective adiponectin level is associated with angiographic coronary disease progression in patients with angina pectoris. , 2008, International journal of cardiology.

[54]  R. Giugliano,et al.  Novel biomarkers in cardiovascular disease: update 2010. , 2010, American heart journal.

[55]  Youichi Kobayashi,et al.  Preventive Effects of Heregulin-&bgr;1 on Macrophage Foam Cell Formation and Atherosclerosis , 2009, Circulation research.

[56]  S. Aydin,et al.  Serum levels of apelin, salusin-alpha and salusin-beta in normal pregnancy and preeclampsia , 2012, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[57]  Xinling Du,et al.  Decreased adiponectin and increased inflammation expression in epicardial adipose tissue in coronary artery disease. , 2011, Cardiovascular diabetology.

[58]  Qinglin Yang,et al.  Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma. , 2007, Journal of molecular and cellular cardiology.

[59]  L. Tian,et al.  Adiponectin reduces lipid accumulation in macrophage foam cells. , 2009, Atherosclerosis.

[60]  P. White,et al.  A Pilot Study to Assess Whether Glucagon-Like Peptide-1 Protects the Heart From Ischemic Dysfunction and Attenuates Stunning After Coronary Balloon Occlusion in Humans , 2011, Circulation. Cardiovascular interventions.

[61]  Qunhua Huang,et al.  Endothelium-Derived Neuregulin Protects the Heart Against Ischemic Injury , 2011, Circulation.

[62]  A. Bikhazi,et al.  Assessment of Glucagon-Like Peptide-1 Analogue and Renin Inhibitor on the Binding and Regulation of GLP-1 Receptor in Type 1 Diabetic Rat Hearts , 2011, Experimental diabetes research.

[63]  N. Marchionni,et al.  Adiponectin in outpatients with coronary artery disease: independent predictors and relationship with heart failure. , 2012, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[64]  R. Shannon,et al.  Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. , 2006, Journal of cardiac failure.

[65]  Yutaka Seino,et al.  Intact glucagon-like peptide-1 levels are not decreased in Japanese patients with type 2 diabetes. , 2010, Endocrine journal.

[66]  D. Dutka,et al.  Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease , 2011, Heart.

[67]  A. Miyazaki,et al.  Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice , 2011, Diabetologia.

[68]  M. Reiser,et al.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques , 2008, PloS one.

[69]  T. Murohara,et al.  Impact of a Single Intracoronary Administration of Adiponectin on Myocardial Ischemia/Reperfusion Injury in a Pig Model , 2010, Circulation. Cardiovascular interventions.

[70]  S. Allahverdian,et al.  Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation. , 2012, Cardiovascular research.

[71]  M. Rizzo,et al.  An update on the role of markers of inflammation in atherosclerosis. , 2010, Journal of atherosclerosis and thrombosis.

[72]  D. Stern,et al.  Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. , 1999, American journal of physiology. Heart and circulatory physiology.