title: Full Expression of Cardiomyopathy Is Partly Dependent on B-Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis.
abstract: BACKGROUND
  Limited information exists on the role of B-cell-dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B-cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP).
  
  
  RESULTS
  CMP protocol involved the use of l-NAME and NaCl in the drinking water and angiotensin-II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild-type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T- and B-cell deficient); CD22(-) CMP (B-cell depleted); and Nude CMP (T-cell deficient), with their respective controls. We performed B-cell depletion and reconstitution protocols. The protective effect of B-cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22(-) CMP group compared to WT CMP. Once SCID mice underwent B-cell reconstitution with isolated CMP B-cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B-cells stimulate collagen production by cardiac fibroblasts.
  
  
  CONCLUSIONS
  The absence of B-cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B-cells play a contributory role in an angiotensin-II-induced HF model.
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.) Houston Methodist Hospital Research Institute, Houston, TX (A.M.C.R., K.A.Y., D.J.H., J.D.E., G.T.A.) Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador (A.M.C.R.).
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cordero-Reyes
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.) Houston Methodist Hospital Research Institute, Houston, TX (A.M.C.R., K.A.Y., D.J.H., J.D.E., G.T.A.).
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: Department of Medicine and Weill Cornell Medical College, Houston Methodist Hospital, Houston, TX (A.R.T., D.J.H.).
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Trevino
authors.affiliation: University of Texas Medical Branch, Galveston, TX (R.C.).
authors.forename: Rene
authors.initials: R
authors.lastname: Celis
authors.affiliation: Houston Methodist Hospital Research Institute, Houston, TX (A.M.C.R., K.A.Y., D.J.H., J.D.E., G.T.A.) Department of Medicine and Weill Cornell Medical College, Houston Methodist Hospital, Houston, TX (A.R.T., D.J.H.).
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Hamilton
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.).
authors.forename: Jose H
authors.initials: JH
authors.lastname: Flores-Arredondo
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.).
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Orrego
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.).
authors.forename: Arvind
authors.initials: A
authors.lastname: Bhimaraj
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.) Houston Methodist Hospital Research Institute, Houston, TX (A.M.C.R., K.A.Y., D.J.H., J.D.E., G.T.A.).
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Estep
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (A.M.C.R., K.A.Y., J.H.F.A., C.M.O., A.B., J.D.E., G.T.A.) Houston Methodist Hospital Research Institute, Houston, TX (A.M.C.R., K.A.Y., D.J.H., J.D.E., G.T.A.) Catedra de Cardiologia y Medicina Vascular, Tecnológico de Monterrey, Mexico (G.T.A.).
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
mesh_terms: D000804:Angiotensin II; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester; D010641:Phenotype; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D012965:Sodium Chloride; D013318:Stroke Volume; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C497868:Cd22 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D051918:Sialic Acid Binding Ig-like Lectin 2; D000804:Angiotensin II; D012965:Sodium Chloride; D003094:Collagen; D019331:NG-Nitroarginine Methyl Ester
keywords: antibodies; cardiomyopathy; immune system; lymphocytes; remodeling