title: Exogenous ubiquitin modulates chronic β-adrenergic receptor-stimulated myocardial remodeling: role in Akt activity and matrix metalloproteinase expression.
abstract: β-Adrenergic receptor (β-AR) stimulation increases extracellular ubiquitin (UB) levels, and extracellular UB inhibits β-AR-stimulated apoptosis in adult cardiac myocytes. This study investigates the role of exogenous UB in chronic β-AR-stimulated myocardial remodeling. l-Isoproterenol (ISO; 400 μg·kg(-1)·h(-1)) was infused in mice in the presence or absence of UB (1 μg·g(-1)·h(-1)). Left ventricular (LV) structural and functional remodeling was studied 7 days after infusion. UB infusion enhanced serum UB levels. In most parts, UB alone had no effect on morphometric or functional parameters. Heart weight-to-body weight ratios were increased to a similar extent in the ISO and UB + ISO groups. Echocardiographic analyses showed increased percent fractional shortening, ejection fraction, and LV circumferential stress and fiber-shortening velocity in the ISO group. These parameters were significantly lower in UB + ISO vs. ISO. Isovolumic contraction and relaxation times and ejection time were significantly lower in ISO vs. UB + ISO. The increase in the number of TUNEL-positive myocytes and fibrosis was significantly higher in ISO vs. UB + ISO. Activation of Akt was higher, whereas activation of GSK-3β and JNKs was lower in UB + ISO vs ISO. Expression of MMP-2, MMP-9, and TIMP-2 was higher in UB + ISO vs ISO. In isolated cardiac fibroblasts, UB enhanced expression of MMP-2 and TIMP-2 in the presence of ISO. Neutralizing UB antibodies negated the effects of UB on MMP-2 expression, whereas recombinant UB enhanced MMP-2 expression. UB activated Akt, and inhibition of Akt inhibited UB + ISO-mediated increases in MMP-2 expression. Thus, exogenous UB plays an important role in β-AR-stimulated myocardial remodeling with effects on LV function, fibrosis, and myocyte apoptosis.
authors.affiliation: Department of Biomedical Sciences, James H. Quillen College of Medicine, James H. Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Daniels
authors.forename: Cerrone R
authors.initials: CR
authors.lastname: Foster
authors.forename: Sana
authors.initials: S
authors.lastname: Yakoob
authors.forename: Suman
authors.initials: S
authors.lastname: Dalal
authors.forename: William L
authors.initials: WL
authors.lastname: Joyner
authors.forename: Mahipal
authors.initials: M
authors.lastname: Singh
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D025801:Ubiquitin / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology*
chemical_list: D011943:Receptors, Adrenergic, beta; D025801:Ubiquitin; D019716:Tissue Inhibitor of Metalloproteinase-2; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9