title: Metallothionein antagonizes aging-induced cardiac contractile dysfunction: role of PTP1B, insulin receptor tyrosine phosphorylation and Akt.
abstract: Aging is often accompanied by reduced insulin sensitivity and cardiac dysfunction. However, the causal relationship between the two remains poorly understood. This study was designed to determine the impact of cardiac-specific overexpression of antioxidant metallothionein (MT) on aging-associated cardiac dysfunction and impaired insulin signaling. Contractile and intracellular Ca(2+) properties were evaluated in left ventricular myocytes including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), fura-2 fluorescence intensity change (DeltaFFI) and intracellular Ca(2+) decay rate. Expression of insulin receptor, protein-tyrosine phosphatase 1B (PTP1B), phosphorylation of insulin receptor (Tyr1146) and Akt were evaluated by Western blot analysis. Aged wild-type FVB and MT transgenic mice (26-28 months old) displayed glucose intolerance and hyperinsulinemia. Cardiomyocytes from aged FVB mice exhibited prolonged TR(90) and intracellular Ca(2+) decay associated with normal PS, +/- dL/dt, TPS and DeltaFFI compared with those from young (2-3 months old) mice. Western blot analysis revealed reduced Akt expression and insulin (5 mU g(-1))-stimulated Akt phosphorylation, elevated PTP1B expression and diminished basal insulin receptor tyrosine phosphorylation associated with comparable insulin receptor expression in aged FVB mouse hearts. All of these aging-related defects in cardiac contractile function and insulin signaling (although not hyperinsulinemia and glucose intolerance) were significantly attenuated or ablated by MT transgene. These data indicate that enhanced antioxidant defense is beneficial for aging-induced cardiac contractile dysfunction and alteration in insulin signaling.
authors.affiliation: Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, 82071, USA.
authors.forename: Cindy X
authors.initials: CX
authors.lastname: Fang
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Doser
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Nair
authors.initials: N
authors.lastname: Sreejayan
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling; D004558:Electric Stimulation; D005453:Fluorescence; D005951:Glucose Tolerance Test; D006352:Heart Ventricles / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D016276:Ventricular Function
chemical_list: D019000:Phosphotyrosine; D008668:Metallothionein; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse